HYPOXIA AND REPRODUCTIVE HEALTH: The role of hypoxia in the development and progression of endometriosis

in Reproduction
Authors:
Wan-Ning Li Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan

Search for other papers by Wan-Ning Li in
Current site
Google Scholar
PubMed
Close
https://orcid.org/0000-0002-2057-885X
,
Meng-Hsing Wu Department of Physiology, National Cheng Kung University, Tainan, Taiwan
Department of Obstetrics & Gynecology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

Search for other papers by Meng-Hsing Wu in
Current site
Google Scholar
PubMed
Close
, and
Shaw-Jenq Tsai Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan
Department of Physiology, National Cheng Kung University, Tainan, Taiwan

Search for other papers by Shaw-Jenq Tsai in
Current site
Google Scholar
PubMed
Close
https://orcid.org/0000-0002-3569-5813

Correspondence should be addressed to S-J Tsai; Email: seantsai@mail.ncku.edu.tw

This paper forms part of a special section on Hypoxia and Reproductive Health. The guest editor for this section was Dr Jacqueline Maybin (University of Edinburgh, UK)

Free access

Sign up for journal news

Endometriosis is a benign gynecological disease that affects about 10% of women of reproductive age. Patients with endometriosis suffer from long-term coexistence with dysmenorrhea, dyspareunia, and even infertility, which severely reduces quality of life. So far, surgical removal and hormonal medication are the major treatment options; however, high recurrence and severe adverse effects hamper the therapeutic efficacy. Hypoxia is an inevitable cellular stress in many diseases that regulates the expression of a significant subset of genes involved in pathophysiological processes. A growing body of evidence demonstrates that hypoxia plays critical role in controlling the disease phenotypes of endometriosis, such as increasing adhesion ability, causing dysregulation of estrogen biosynthesis, aberrant production of proinflammatory cytokines, increasing angiogenic ability, and suppression of immune functions. In this review, we summarize the findings of the most recent studies in exploring the underlying mechanisms of hypoxia involved in endometriosis. Potential therapeutic options for targeting HIF and downstream effectors will also be discussed.

Abstract

Endometriosis is a benign gynecological disease that affects about 10% of women of reproductive age. Patients with endometriosis suffer from long-term coexistence with dysmenorrhea, dyspareunia, and even infertility, which severely reduces quality of life. So far, surgical removal and hormonal medication are the major treatment options; however, high recurrence and severe adverse effects hamper the therapeutic efficacy. Hypoxia is an inevitable cellular stress in many diseases that regulates the expression of a significant subset of genes involved in pathophysiological processes. A growing body of evidence demonstrates that hypoxia plays critical role in controlling the disease phenotypes of endometriosis, such as increasing adhesion ability, causing dysregulation of estrogen biosynthesis, aberrant production of proinflammatory cytokines, increasing angiogenic ability, and suppression of immune functions. In this review, we summarize the findings of the most recent studies in exploring the underlying mechanisms of hypoxia involved in endometriosis. Potential therapeutic options for targeting HIF and downstream effectors will also be discussed.

Introduction

Endometriosis is a common gynecological disease characterized by endometriotic lesions growing outside of the uterine cavity. Endometriotic lesions are commonly seen on the wall of the peritoneum and the surface of the ovaries and cause clinical symptoms, such as pelvic pain during menstruation, dyspareunia, and infertility. The overall prevalence of endometriosis is around 6–10% in women of reproductive age; however, it is generally believed the number is underestimated due to diagnostic limitations of laparoscopy and a proportion of asymptomatic women. Although endometriosis is considered to be a nonlethal disease, clinical symptoms, together with the heavy financial burden, amounting to an average of thousands of dollars per person per year (Soliman et al. 2016), severely reduces patients’ life quality. Surgical removal is the gold-standard treatment for patients with endometriosis; however, a report has shown that the recurrence rate after surgical removal is unsatisfactorily high (Cea Soriano et al. 2017). Hormonal-based medication is an alternative for treating endometriosis, but the main purpose of this is to ease endometriosis-associated pain instead of curing it. These clinical facts suggest that treatments available so far are not able to thoroughly cure the disease and there are unmet medical needs to develop more efficacious treatment regimens.

The etiology of endometriosis is enigmatic. It is reported that the development of endometriosis is contributed by multiple gene–gene and gene–microenvironmental factors. According to Sampson’s theory, the presence of endometriotic tissues in the peritoneal cavity is associated with retrograde menstrual dissemination (Sampson 1927). Sampson hypothesized that endometriotic lesions are originated from the shed endometrial tissues of the uterus, which, along with the retrograde flow, move to the ectopic sites. However, retrograde menstruation happens in over 90% of women during their cycles (Halme et al. 1984) but only 10% of them develop endometriosis, suggesting there must be other critical factors that determine the disease progression.

Hypoxia is the first stress that these retrograde tissues encounter. Without enough oxygen and nutrients supplied, most of the cells die. However, some cells in the endometriotic lesions undergo epigenetic changes through unclarified mechanisms, and not only show good vitality under hypoxic stress, but also exhibit a capability for further growth (Wu et al. 2019). Despite originating from the endometrium, it is considered that those migrated endometrial cells undergo large phenotypic changes that benefit their own survival and adapt themselves to the microenvironment. Many studies have indicated that the unexpected alteration is due to dysregulation of hormones and impairment of the immune system, yet there is still no comprehensive explanation for the etiology, since endometriosis is not a disease of mutation.

Hypoxia-inducible factors (HIFs), which are heterodimeric complexes constituting α and β subunits, work as transcriptional factors to regulate the expression of their target genes under hypoxia. The β subunit (HIF-1β), also known as aryl hydrocarbon nuclear translocator, constitutively expresses under both normoxic and hypoxic conditions, while α subunits (HIF-1α and HIF-2α) only exist under hypoxia. Under ambient oxygen, HIF-α undergoes 26S proteasome degradation due to hydroxylation modification on its oxygen-dependent degradation domain, while under the low-oxygen condition, accumulated HIF-α dimerizes with HIF-1β and further regulates the genes with hypoxia response element (Semenza 2007). CREB binding protein and p300 are co-activators that bind to the transactivation domain of HIF-1α, and they are also found to be essential for HIF transcriptional activity during hypoxia. It has been reported that endometriotic stromal cells showed elevated HIF-1α expression (Wu et al. 2007), and HIF-1α directly regulates a number of genes at the transcriptional level (Wu et al. 2011, Lin et al. 2012, 2017), indicating there is a high possibility that the involvement of hypoxia in endometriosis is through HIF-1α regulation.

Through mediating gene expression, hypoxia regulates a broad range of biological processes such as cell proliferation, angiogenesis, apoptosis, immunology, and tumor metastasis as well as drug resistance. Herein, we summarize papers published to date to discuss the regulatory role of hypoxia in the development and progression of endometriosis.

Hypoxia as the force of endometriosis

The involvement of hypoxia during the development of endometriosis was not studied until 2007, when Wu et al., first reported the upregulation of HIF-1α mRNA and protein in endometriotic lesions and its transcriptional activity in inducing leptin expression (Wu et al. 2007). It is conceivable that the retrograde tissues originating from the endometrium may encounter many challenges in the peritoneal cavity, including lack of oxygen, immune attack, mechanical damage, or other environmental stress. Despite so many difficulties, it seems that endometriotic tissues are able to overcome these hurdles in the microenvironment by utilizing hypoxia as the driving force. In the following sections, we will briefly classify the processes during the development of endometriosis into three sections, namely early-stage lesion implantation and survival, the immune clearance system, and disease progression, in order to discuss the role of hypoxia (Fig. 1). Moreover, we will also focus on the effect of hypoxia-mediated epigenetic modification in the pathogenesis of endometriosis in the last part.

Figure 1
Figure 1

Schematic drawing shows the pathophysiological effects of hypoxia during the development and progression of endometriosis.

Citation: Reproduction 161, 1; 10.1530/REP-20-0267

Role of hypoxia during early-stage implantation of endometriosis

During the early period of endometriosis development, acquiring abilities of migration, adhesion, and invasion into the peritoneum or other sites is a prerequisite for the retrograded cells to implant and survive. In addition, as energy utilization is also extremely important at this difficult time, so as a result, the regulation of apoptosis, autophagy and metabolic changes are all crucial for maintaining cell viability. A number of studies have emphasized the importance of hypoxia involvement in mediating the pathophysiological processes during early endometriosis development. Herein, we summarize the previous findings to discuss the regulatory mechanisms of hypoxia involved in cell adhesion, migration/invasion, apoptosis, autophagy, and metabolism in endometriosis.

Cellular adhesion

Cells with higher adhesive ability have advantages in early-stage development of endometriosis (Choi et al. 2017). Recent studies showed that hypoxia induces several key genes to enhance the adhesive ability of endometriotic cells (Lin et al. 2018, 2019). According to Sampson’s retrograde menstruation theory, endometriotic lesions in the peritoneal cavity are brought by the retrograde flow (Sampson 1927). Theoretically, the floating tissues, without nutrient supply and physical support from the extracellular matrix, are not able to survive under these conditions. However, studies have revealed that endometriotic tissues show increased adhesive ability (Lin et al. 2019), which has been suggested as one of the critical factors to sustain survival in the early stage. In fact, severe adhesion in the peritoneal cavity is a condition that is commonly seen in clinical patients, and is one of the leading causes of pelvic pain and infertility (Stout et al. 1991, Cheong et al. 2001), and this provides a hint that cellular adhesion is involved not only in the early stage, but throughout the entire course of endometriosis. Certain kinds of adhesion molecules are found to be highly expressed in endometriotic lesions, such as integrins (Lessey et al. 1994), CD44 (Griffith et al. 2010), cell adhesion molecules (Vigano et al. 1998, Kuessel et al. 2017), and other adhesion-related molecules such as proprotein/matrix metallopeptidases (MMPs) (Pino et al. 2009). Chronic inflammation and hypoxia are regarded as two major factors responsible for better cell adhesive ability in endometriotic stromal cells. For instance, transforming growth factor-β1 (TGF-β1), which mainly participates in tissue remodeling, wound healing, and fibrotic responses, is found to be elevated in peritoneal fluid from patients with endometriosis (Kupker et al. 1998). TGF-β1 is reported to induce peritoneal adhesion through increasing αV, α6, β1, and β4 integrins in an endometrial cell line (Choi et al. 2017) and in a mouse model of endometriosis (Soni et al. 2019). More interestingly, Lin et al. reported TGF-β1-stimulated integrin expression is a result of the hypoxic effect, finding that HIF-1α stabilization could enhance the level of SMAD2/SMAD3 phosphorylation in primary endometrial stromal cells (Lin et al. 2018). Recently, membrane-expressed anthrax toxin receptor 2 (ANTXR2) was shown to be a novel adhesion-related molecule (Bell et al. 2001, Lin et al. 2019). ANTXR2 is highly expressed in endometriotic stromal cells and is mediated by hypoxia. Hypoxia decreases enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 (H3K27) methylating enzyme, leading to the reduction of trimethylated H3K27 in ANTXR2 promoter and resulting in transcriptional upregulation of ANTXR2 in endometriotic stromal cells. Furthermore, treatment with 1, 2, 3, 4, 6 -penta-O-galloyl-β-D-glucopyranose, an ANTXR2 inhibitor, abolishes hypoxia-induced increased cell migration and adhesion. An animal model also demonstrated that blocking ANTXR2 signaling not only prevents endometriotic lesion development but also causes the established lesion to be regressed (Lin et al. 2019). These findings suggest that targeting ANTXR2 can be used in both preventive and therapeutic regimens for endometriosis.

Migration/invasion

It was hypothesized that the destruction of the mesothelium layer is a consequence of invasion and migration of endometriotic cells; however, the underlying mechanism remained to be elucidated. Later, it was indicated that the damaged mesothelial basement membrane at the peritoneum surface is the site of preference for the attachment of endometrial fragments (Burney & Giudice 2012). Despite the fact that endometriosis is a benign gynecological disease, many studies have indicated that endometriotic cells shared the characteristics of malignant tumors. Some reports have indicated that the malignancy-like abilities of these refluxed endometrial stromal cells lead to tissue remodeling in the mesothelial layer (Ishimaru et al. 2004, Sotnikova et al. 2010), facilitating the implantation of endometriotic lesions. Taking enzyme proteins as an example, the ratio of inactivated and activated MMPs, as well as the imbalance between the levels of MMPs and tissue inhibitor of metalloproteinase, have been found to be important for the regulation of cellular migration and invasion in endometriosis (Bruner-Tran et al. 2002). It has been reported that both MMP2 and MMP9 are elevated in endometriotic stromal cells, and they can be regulated by a variety of factors, including tumor necrosis factor-α (TNF-α) (Pino et al. 2009) and prostaglandin (PG) E2 (Jana et al. 2016). Hypoxia is regarded as the upstream regulator that strengthens endometriotic cells to be more invasive. Wu et al. showed hypoxia could induce the levels of leptin (Wu et al. 2007) and PGE2 (Wu et al. 2011), two modulators shown to enhance cell invasion through mediating the expression of MMP2 in stromal cells. Additionally, hypoxia could also promote cell migration through causing the loss of CD26/dipeptidyl peptidase IV, which is also a peptidase complex involved in enzymatic reactions in cellular remodeling (Tan et al. 2014). As mentioned previously, Lin et al., reported that hypoxia-induced ANTXR2 upregulation in endometriotic stromal cells also contributes to cell migration (Lin et al. 2019).

Cell survival anti-apoptosis

Apoptosis is a type of programmed cell death commonly seen in many physiological conditions, which is important for maintaining cellular homeostasis during embryonic development (Fuchs & Steller 2011), organ formation (Lindsten et al. 2000), tissue remodeling (Gosden & Spears 1997), and so on. Reduced apoptosis is observed in endometriotic stromal cells (Delbandi et al. 2020) and hypoxia was reported to play some roles in this biological process, which may explain why endometriotic lesions in patients showed better survival. B-cell lymphoma 2 (Bcl-2), which serves as a blocker for apoptotic deaths, was the most studied apoptosis-related protein in early research (McLaren et al. 1997, Watanabe et al. 1997). It has been reported that Bcl-2 is cyclically expressed in human endometrium (Watanabe et al. 1997); however, the level of Bcl-2-positive cells in endometriotic stroma showed significantly higher levels than that in paired endometrial tissue, and also had no connection with menstrual phases (Harada et al. 1996, McLaren et al. 1997, Jones et al. 1998). Note that the ‘Bcl-2-positive cells’ described here include tissue macrophages (McLaren et al. 1997) and non-leukocytic stromal cells (Jones et al. 1998) in ectopic lesions, and both of these two cell types are enrolled in the anti-apoptotic function in endometriosis.

The involvement of the Fas/Fas ligands (FasL) system in endometriosis is still under debate. Harada et al. and Watanabe et al. considered that Fas, the receptor, may be less important in regulating the development of human endometriosis due to there being no expression change between eutopic and ectopic tissues (Harada et al. 1996, Watanabe et al. 1997). On the other hand, increased soluble FasL was found in both serum and peritoneal fluids from patients with endometriosis, which suggested that differentially expressed ligand is important in endometriosis. To investigate the key drivers in dysregulating apoptosis in endometriosis, most reports focus on the enriched protein factors that have been found in the peritoneal fluid of women with endometriosis. IL-8, chemokine ligand 2 (CCL2), and extracellular matrix molecules such as laminin, fibronectin, and collagen IV, are the inducers of FasL in endometriosis (Selam et al. 2006), stimulating the apoptosis reaction in cytotoxic T cells in the peritoneal cavity, and thus further enhancing the implantation of endometriotic lesions. Additionally, estrogen receptor (ER)-β is reported to inhibit caspase-8 and caspase-9 activation to prevent the extrinsic and intrinsic apoptosis signaling in a mouse model of endometriosis (Han et al. 2015). In fact, hypoxia is a potent modulator of IL-8 (Hsiao et al. 2014) and ER-β (Wu et al. 2012), which suggests that hypoxia may also be important in mediating the apoptosis reaction in endometriotic lesions. Moreover, it has been demonstrated that cyclooxygenase (COX)-2-derived PGE2 could activate the EP2/EP4 receptor to prevent cells from undergoing apoptosis in human endometriotic stromal cells (Banu et al. 2008). As COX-2 is upregulated by hypoxia (Wu et al. 2011), it is possible that endometriotic cells are more apoptosis-resistant due to a hypoxia-mediated gene expression. Other lines of evidence also showed that hypoxia mediates the expression of IL-6 via dual-specificity phosphatase 2 (DUSP2) suppression, which further enhances STAT3 activation to act against cell apoptosis in endometriotic stromal cells (Hsiao et al. 2017a).

Cell survival autophagy

The role of autophagy machinery in cell physiology is multifaceted. Autophagy is a constitutive process for energy conversion and will be induced particularly when cells encounter oxidative stress or other hostile conditions such as hypoxia (Yu et al. 2018). Mediated by a number of proteins that are involved in composing phagophores and lysosome fusion, phagosome and phagolysosome subsequently form for the purpose of obtaining more energy for survival by degrading some endogenous long-lived proteins. Moderate autophagy is beneficial for cell survival, yet both excessive and insufficient autophagic activity can be harmful for maintaining cellular homeostasis. Phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin (mTOR) signaling are the dominant pathways in regulating autophagy which is mostly involved in activating autophagy-related proteins and further enhancing microtubule-associated protein light chain 3 (LC3) lipidation. Most studies have suggested that the activity of autophagy, with no cyclical difference, is repressed in both ectopic stromal and epithelial cells in endometriosis by the hormonal effect (Choi et al. 2014, Mei et al. 2015). In contrast, other studies showed upregulation of autophagy in endometriosis, in which they indicated this defense mechanism is induced in order to prevent endometriotic cells from dying (Liu et al. 2017). A series of studies done by Liu’s group not only demonstrated that the autophagic response in endometriosis is stimulated by hypoxia, but also found that HIF-1α is a critical factor that promotes LC3 lipidation in human endometriotic stromal cells (Liu et al. 2017, 2018). Moreover, hypoxia-induced autophagy is also a driver for epithelial-to-mesenchymal transition (EMT) that enhances cell migration and invasion abilities during the development of endometriosis (Liu et al. 2017, 2018).

Cell survival metabolic changes

The metabolic pattern of endometriotic cells is largely different from that in eutopic cells. It has been reported that endometriotic cells display a Warburg-effect-like phenotype, which showed a tendency of undergoing aerobic glycolysis. Indicators of glycolysis such as pyruvate dehydrogenase kinase 1 (PDK1) and lactate dehydrogenase A (LDHA) are found to be more highly expressed in endometriotic lesions than in the normal endometrium (Young et al. 2016, Lee et al. 2019). Moreover, lactate production is also increased in endometriotic stromal cells (Lee et al. 2019), which shows a high similarity with tumor cells. HIF-1α, the well-known modulator of cellular metabolism, was demonstrated to regulate the expression of genes in endometriotic stromal cells that are associated with glycolysis (Lee et al. 2019), suggesting hypoxia plays a critical role in transforming cellular characteristics in glucose metabolism.

Hypoxia impairs immuno-clearance system in endometriosis

Endometriosis is a chronic pelvic inflammatory disease that is characterized by high levels of proinflammatory cytokines in the peritoneal cavity. A variety of immune cells are found to be recruited to the endometriotic lesions, and the presence of these cells has been demonstrated to be beneficial for the growth of endometriotic tissues (Wu et al. 2002b, Li et al. 2014). More precisely, the functions of peritoneal leukocytes which are supposed to fight against invaders, the retrograded endometriotic tissues, are weakened due to some unclarified mechanisms which may be the cause and the effect of chronic inflammation in the peritoneal cavity (Raiter-Tenenbaum et al. 1998).

It has already been demonstrated that peritoneal macrophages are highly infiltrated in endometriotic implants (Wu et al. 2002b, Lin et al. 2006). Macrophages are regarded as the first-line defender during the primary immune response (Gordon 1998), showing the phagocytic ability to fight against pathogens and to eliminate cell debris for the maintenance of tissue integrity. Macrophages can be roughly classified into M1 and M2 phenotypes, which show a large difference in their immune functions, including the ability of phagocytosis and the types of cytokines released. Polarized macrophages exert distinct functions during inflammation and the development of disease pathogenesis (Mosser & Edwards 2008). For instance, the M1 macrophage is the classical phenotype of a macrophage which is characterized by the aggressive eliminating ability for the enhancement of proinflammation; meanwhile, the M2 macrophage is found to be incapable of getting rid of pathogens, and is usually considered as a brake during strong inflammation. The balance between M1 and M2 macrophages is important in order to maintain the normal immune function in the human body. However, without a clear mechanism, the phagocytes around ectopic tissues exhibit less aggressive characteristics as well as impaired function of recognition and engulfment (Raiter-Tenenbaum et al. 1998), a phenotype similar to M2 macrophages. It has been reported that the impairment of peritoneal macrophages is one of the main factors responsible for the presence of endometriotic lesions outside of the uterine cavity (Loh et al. 1999).

Hormonal dysregulation is one of the major causes that worsen the immune surveillance system in patients with endometriosis. Estrogen stimulates endometrial stromal cells to produce monocyte chemotactic protein-1, which enhances macrophage infiltration and activation (Akoum et al. 2000). A number of studies have mentioned that estrogen impairs the immune system via affecting M1/M2 polarization and the phagocytic ability of macrophages (Veillat et al. 2012). Aberrant expression of ER-β of endometriotic stromal cells is also found to affect the distribution of macrophages (Greaves et al. 2015). It has been demonstrated that the highly expressed ER-β in endometriotic stromal cells promotes CCL2 secretion via NF-кB signaling, which increases the recruitment of macrophages with M2 phenotype around endometriotic lesions (Gou et al. 2019). Apart from estrogen, prostaglandins are also reported to regulate the immune function of macrophages in endometriosis. A series of studies from our group demonstrates that PGE2 suppresses the phagocytic ability of peritoneal macrophages by the inhibition of MMP-9 expression and activation (Wu et al. 2005a), CD36-dependent phagocytosis (Chuang et al. 2010), and Annexin A2-mediated phagocytosis (Wu et al. 2013), providing evidence to explain the dysfunction of immune cells during the development of endometriosis.

Many studies indicated that hypoxia is the master modulator that regulates the function of macrophages in endometriosis. It has already been demonstrated that the expression of estrogen receptors in endometriosis are regulated by hypoxia (Wu et al. 2012). Hypoxia stimulates the expression of ER-β and knockdown of HIF-1α significantly increases the expression of ER-α and downregulates the level of ER-β in primary endometriotic stromal cells (Wu et al. 2012). Evidence has also indicated that hypoxia could upregulate PGE2 via inducing the secretion of COX-2 in endometriosis (Wu et al. 2005b). Moreover, the abnormally expressed leptin in endometriotic cells (Wu et al. 2007), a kind of adipokine that also serves as an immunomodulator, is also reported to be upregulated by HIF-1α stabilization, and could mediate the function of peritoneal macrophages through affecting the expression of PGE2 (Wu et al. 2010). Overall, hypoxia is a strong regulator that affects the immune function of peritoneal macrophages in endometriosis, which subsequently enhances the survival of endometriotic lesions in the peritoneal cavity.

Role of hypoxia in endometriotic lesion growth

To maintain a long-term survival, the retrograde endometriotic tissues equip themselves with some particular characteristics which improve their living conditions, such as capabilities of angiogenesis and proliferation. Both endometriotic lesions and the members in the microenvironment are found to release pro-survival factors to promote lesion growth. Hypoxia is known as a strong factor for promoting angiogenesis, cell proliferation, and even metastasis in cancer cells (Chen et al. 2020). Similarly, the growth of endometriotic lesions is also largely affected by the hypoxic force. The following part will further discuss the role of hypoxia in regulating factors involved in living maintenance.

Angiogenesis

The first problem that the temporarily survived endometriotic cells will encounter is how to get enough oxygen and nutrients to sustain further life. In addition to increasing autophagy to obtain more energy or transforming metabolic phenotype to change the energy utilization method, endometriotic tissues are also found to possess a higher level of angiogenesis activity to provide routes for blood transportation. Angiogenesis is a process that generates new vessels extending from the pre-existing vasculature structure, allowing the delivery of more nutrition and oxygen to neighboring tissues. The angiogenic activity is modulated by multiple factors, and a large proportion of them are found to be dysregulated in endometriosis, primarily due to hypoxic stress (Wu et al. 2019). Vascular endothelial growth factor (VEGF)-A and angiogenin, the widely known factors that mainly participate in angiogenesis, are highly expressed in endometriotic cells (Fasciani et al. 2000, Fu et al. 2018). Immune factors involved in chronic inflammation also takes part in proangiogenic development. Elevated levels of proinflammatory cytokines in the peritoneal cavity such as IL-1β, TNF-α, and TGF-β, are all proved to induce angiogenic activity in endometriotic tissues. Additionally, angiogenesis in endometriosis could also be activated by certain kinds of chemokines, and IL-8, the most studied chemokine in endometriosis, serves as a strong inducer in the angiogenic process (Fasciani et al. 2000, Hsiao et al. 2014).

Hypoxia was demonstrated to be the upstream factor that regulates angiogenesis in endometriosis (Fig. 2). Upregulation of VEGF-A (Sharkey et al. 2000), IL-6 (Hsiao et al. 2017a), and IL-8 (Hsiao et al. 2014) are reported to be associated with the hypoxic stress or HIF-1α stabilization. Two regulators that are involved in hypoxia-mediated angiogenesis in endometriosis are DUSP2 and chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII). DUSP2 is a phosphatase that negatively regulates ERK signaling, an important signaling pathway showing an extensive effect on cellular functions. Therefore, it is not surprising to find that the downregulation of DUSP2 in endometriosis enhances the disease progression (Lin et al. 2012). Levels of DUSP2 are markedly suppressed by hypoxia in endometriotic stromal cells (Wu et al. 2011). Angiogenesis-related genes such as IL-6 (Hsiao et al. 2017a), IL-8 (Hsiao et al. 2014), early growth response protein-1 (EGR-1), cysteine-rich angiogenic inducer 61 (CYR61), and osteopontin (Lin et al. 2012) are stimulated by hypoxia through DUSP2 downregulation. COX-2, the rate-limiting enzyme for PGE2, is also induced by hypoxia-suppressed DUSP2 (Wu et al. 2011), which further promotes angiogenesis in endometriosis. On the other hand, COUP-TFII is an orphan nuclear receptor that is critically involved in embryo development and cardiovascular-related functions. Fu et al. demonstrated hypoxia suppressed the expression level of COUP-TFII in endometriosis, which further drives angiogenesis through the increasing level of angiogenin (Fu et al. 2018). Moreover, suppression of COUP-TFII could also promote the COX-2 expression in endometriotic stromal cells (Lin et al. 2014) to induce the PGE2 production for tissue angiogenesis.

Figure 2
Figure 2

Hypoxia-regulated signaling pathways leading to angiogenesis in endometriosis. Adapted with permission from Fig. 2 from the article ‘Hypoxia: The force of Endometriosis’ published in ‘J. Obstet. Gynaecol. Res. Vol. 45, No. 3: 532–541, March 2019’.

Citation: Reproduction 161, 1; 10.1530/REP-20-0267

Cell proliferation

Endometrial cells from patients with endometriosis showed a more persistent proliferative capacity than that from disease-free women (Klemmt et al. 2007). It is known that the disequilibrium between cellular apoptosis and proliferation may lead to the cell overgrowth or tissue damage. In endometriosis, the retrograde endometrial tissues are featured with increased proliferation and decreased apoptosis (Wing et al. 2003, Lee et al. 2019), which consequently contributes to the tissue growth. Certain genes related to cell proliferation or survival are found to be increased in endometriotic implants when compared to paired eutopic tissues. Differentially expressed estrogen receptors in endometriotic cells, which show higher ER-β than ER-α, are found to have a higher proliferative ability (Han et al. 2015). The attachment to specific ECM components such as laminin, fibronectin, and vitronectin, significantly induces DNA synthesis in endometriotic stromal cells, suggesting adhesion could further enhance cell proliferation in endometriosis (Klemmt et al. 2007). Besides those, peptide growth factors are supposed to mediate the proliferation of endometriosis. Several peptide growth factors, such as EGF (Huang et al. 1996), insulin-like growth factor (Sbracia et al. 1997), leptin (Wu et al. 2002a), and fibroblast growth factor (FGF) (Wing et al. 2003) are proposed to be good candidates to stimulate endometriotic lesion growth. Among these, FGF-9 is the best characterized and least argued one. FGF-9 is a potent endometrial stromal cell growth factor and its expression fluctuates with the menstrual cycle with a peak at the late proliferating phase, which is correlated with the concentration of estrogen (Tsai et al. 2002). Indeed, FGF-9 is an estromedin that mediates estrogen-stimulated endometriotic stromal cell proliferation (Wing et al. 2003). In endometriosis, FGF-9 and its cognate receptors are all expressed in endometriotic stromal cells and are functional (Wing et al. 2003). FGF-9 binds to FGFR2IIIc and FGFR3IIIc in endometrial stromal cells to stimulate protein expression, an essential step for cell differentiation and proliferation, through mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase pathways (Wing et al. 2005). More interestingly, FGF-9 is not only upregulated by PGE2-induced estrogen (Wing et al. 2003) but also directly by PGE2 through a different PGE2 receptor-mediated signaling pathway in endometriotic stromal cells (Chuang et al. 2006). Since the aberrant production of PGE2 is a result of hypoxia-mediated COX-2 overexpression, it is likely that overexpression of FGF-9 in endometriotic stromal cells is initiated by hypoxic stress. Indeed, it has been shown that hypoxia can upregulate the FGF-9 protein level via DUSP2-COX-2-PGE2 cascade (Wu et al. 2011), microRNA-20a-COX-2 pathway (Lin et al. 2012) and in Yes-associated protein 1 (YAP1)-dependent pathway (Lin et al. 2017). These data clearly indicate that hypoxia-induced, FGF-9-mediated cell proliferation is a major factor for endometriosis development and progression; further studies focusing on disrupting FGF-9/FGFR signaling may lead to the discovery of alternative endometriosis treatment strategies.

Epigenetics and noncoding RNA

Epigenetic regulations such as DNA methylation and ncRNA expression result in distinct gene expression patterns in cells, which may explain why the same DNA sequence in a lineage of cells can generate different phenotypes in normal and abnormal cell populations. Through modifying the structure of DNA or RNA, the stringently controlled process is reported to be powerful; indeed, studies have indicated the modifications at the molecular level play critical roles in regulating cellular homeostasis, and even disease progression. Hypoxic stress is a strong force that drives a number of gene expression changes, and its role in modulating the molecular structure of both DNA and RNA in disease pathogenesis has been greatly emphasized. Since there is no evidence demonstrating that endometriosis is caused by germline mutation, it is suggested that endometriosis is an epigenetic disease (Guo 2009). The following section will summarize how hypoxia regulates the pathogenesis of endometriosis via epigenetic modulation.

DNA methylation

Modulation of DNA methylation plays an important role in chromatin remodeling and transcriptional regulation. The major form of DNA methylation in mammalian cells is 5-methyl cytosine, of which the formation and maintenance is mainly controlled by DNA methyltransferases (DNMTs)-1, -3a, and -3b. DNMT1 favors hemi-methylated DNA as a substrate and transmits the methyl markers from passage to passage. Both DNMT3a and 3b generate new DNA methylation sites using the unmethylated templates as substrates. In endometriosis, there are studies demonstrating that certain genes such as ER-β (Xue et al. 2007a), aromatase (Izawa et al. 2011), and steroidogenic factor-1 (Xue et al. 2007b) are hypomethylated at their promoters, leading to aberrant expression of these genes in endometriotic cells. In contrast, hypermethylation of ER-α, leading to reduced expression of ER-α in ovarian endometrioma, was also reported (Maekawa et al. 2019). A genome-wide DNA methylation study shows that 403 genes were found significantly different in CpG island methylation when comparing the modification status between endometriotic and normal endometrial stromal cells (Dyson et al. 2014). A recent study shows that endometriotic stromal cells express less DNMT1 and have a lower 5-methylcytosine level than normal endometrial stromal cells (Hsiao et al. 2015). The molecular mechanism responsible for global downregulation of DNMT1 was also revealed (Fig. 3). Hypoxia recruits AU-rich element binding factor 1, a mRNA destabilizing RNA-binding protein, and microRNA-148a (miR-148a) onto the 3’ UTR of DNMT1 mRNA to cause the degradation of DNMT1 mRNA. The authors further demonstrated that suppression of DNMT1 by hypoxia for 3 days results in aberrant gene expression in normal endometrial stromal cells (Hsiao et al. 2015). These data provide solid evidence to support the notion that hypoxia can regulate gene expression via altering the DNA methylation pattern during the development of endometriosis.

Figure 3
Figure 3

Involvement of hypoxia in epigenetic regulation in the pathogenesis of endometriosis.

Citation: Reproduction 161, 1; 10.1530/REP-20-0267

Histone modification

Histone modifications and DNA methylation are two dominant regulatory pathways in cellular epigenetics. Covalent modifications of histones are differentially expressed in endometriotic lesions (Samartzis et al. 2013, Monteiro et al. 2014). Monteiro et al. showed acetylation of histones in endometriotic tissues is globally decreased particularly at the site of histone 3 (Monteiro et al. 2014). Concomitantly, histone deacetylase 1 (HDAC1) is found to be increased both in endometriotic epithelial and stromal cells (Samartzis et al. 2013). Treatment with HDAC inhibitor (HADCi) successfully enhances the acetylation of histones on the promoter of genes related to cell cycle checkpoints in endometriotic stromal cells, which further induces cell cycle arrest and cellular apoptosis (Kawano et al. 2011). In contrast, by reanalyzing microarray data deposited in Gene Expression Omnibus (Hever et al. 2007), Lin et al., discovered that the groups of polycomb repressive complex 2 proteins including EED, RBBP4, SUZ12 and EZH2, were all decreased in the endometriotic tissues compared to their eutopic counterparts (Lin et al. 2019). Experimental characterization also showed that EZH2 is downregulated in endometriotic stromal and epithelial cells, which results in a global decrease of trimethylated H3K27, a suppressive mark for gene expression, in endometriotic cells (Fig. 3). Hypoxia is the driving force to cause the downregulation of EZH2 and concomitantly overexpression of a group of genes involved in cell adhesion, proliferation, migration, and angiogenesis (Lin et al. 2019).

Non-coding RNAs

Noncoding RNAs are single-strand RNA which can be roughly classified by the length: small ncRNA and long ncRNA. In the category of small ncRNA, miRNAs are widely known to be involved in many pathological processes by modulating their target mRNAs. Hypoxia has been shown to regulate the biogenesis of miRNAs (Liao et al. 2014). Generally, miRNA is able to mediate mRNA stability through binding to the seed region of 3’UTR in a post-transcriptional manner. As for the long ncRNA (lncRNA), which is defined as having a transcript’s length over 200 bases, the major function is to serve as a sponge for miRNA or regulator of transcription. The third kind of ncRNA is circular RNA (circRNA), of which length can be shorter or longer than 200 bases. The functions of ncRNAs as epigenetic regulators are multifaceted. For instance, circRNAs can serve as regulators of transcription, as intermediates in RNA processing reactions, or as sponges for targeted miRNAs (Hsiao et al. 2017b). In recent decades, due to the advance of techniques, both miRNAs and lncRNAs have emerged as novel regulators in endometriosis (Teague et al. 2010). However, most papers report aberrant expression (up- or downregulation) of them and subsequent impacts on target genes’ expression without investigating how these noncoding RNAs are regulated. Recently, hypoxia has been considered as one of the major factors to modulate the expression of noncoding RNA in endometriosis. For instance, it has been reported that hypoxia promotes autophagy activity in endometriotic stromal cells via direct association between HIF-1α and miR-210 (Xu et al. 2016). In addition, a report showed that hypoxia-regulated autophagy can also be mediated via long ncRNA (Liu et al. 2019). Angiogenesis is an important process in endometriotic lesion development and is found to be mediated by hypoxia-induced miRNAs. MiR-20a (targets DUSP2), miR-302a (targets COUP-TFII), miR-199a (targets VEGF-A), miR-148a (targets DNMT1), and miR-210-3p (targets BARD1) are all regulated by hypoxia (Lin et al. 2012, 2014, Hsu et al. 2014, Hsiao et al. 2015, Dai et al. 2019) and play critical roles in endometriosis pathophysiological processes. Interestingly, hypoxia regulation of miRNAs can be via upregulation (miR-20a, miR-210-3p), downregulation (miR-199a), or recruiting it to the targeted mRNA 3’UTR (miR-148a).

Targeting hypoxia-mediated gene regulatory network as therapeutic strategies

As hypoxia is a potent regulator in the pathogenesis of endometriosis, blocking the hypoxic effect is considered to be an ideal therapeutic strategy for treating this disease. Some studies reported that targeting HIF-1α protein in endometriosis mice could successfully suppress the lesions growth via the inhibition of vascular permeability (Becker et al. 2008). Using HADCi could also show anti-angiogenic effect in endometriotic cells by reducing the expression of both HIF-1α and VEGF (Imesch et al. 2011). Additionally, signaling blockers such as Sorafenib and Rapamycin are effective to reduce the level of HIF-1α, and further restricting the development of endometriosis (Moggio et al. 2012). However, HIF-1α is critical not only for the pathological abnormalities but also for normal physiological functions; thus, targeting HIF-1α may not work for benign diseases such as endometriosis.

Besides targeting HIF-1α, interventions in downstream target genes of HIF-1α are also alternative ways for treating endometriosis. As mentioned previously, elevated YAP1 expression has been found in endometriotic stromal cells (Joshi et al. 2016, Song et al. 2016, Lin et al. 2017), and this is a promising target for future clinical therapy. Increased YAP1 is found to promote cell proliferation and prevent cells from undergoing apoptosis in endometriosis (Song et al. 2016, Lin et al. 2017). Verteporfin, an YAP1 inhibitor, could successfully block steroidogenesis, cell proliferation, angiogenesis, proinflammatory cytokine production, and invasion in an endometriosis mouse model, without compromising the fertility of female mice (Lin et al. 2017). Blocking hypoxia-induced ANTXR2 also showed a beneficial effect on lesion regression in an endometriosis mice model (Lin et al. 2019).

Conclusion

A growing body of evidence suggests that the development of endometriosis is considerably affected by hypoxic stress. Owing to the effect of stabilized HIF-1α under hypoxia, many genes involved in the pathological conditions of endometriosis are found to be directly regulated at the transcriptional level. In addition, hypoxia could also affect certain genes indirectly through epigenetic regulation such as DNA methylation, histone modification, or miRNA-mediated post-transcriptional mRNA destabilization. So far, major clinical options for treating patients with endometriosis are surgery and hormonal drug medication. However, the high recurrence rate and severe adverse effects nevertheless continue to be problems. Since endometriosis is a disease of complicated etiology, a single treatment method may not be an effective cure. Based on the findings so far, it is believed that hypoxia strongly modulates the pathological processes in endometriosis. Hence, considering targeting the hypoxia-mediated gene regulatory network in clinical therapy as a combinatorial treatment may be a promising strategy in the future.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work was supported by grants from Ministry of Science and Technology, Taiwan (MOST 108-2321-B-006-006 and 108-2314-B-006-059-MY3).

Author contribution statement

W N Li, M H Wu, and S J Tsai wrote the draft this article. W N Li and S J Tsai revised and finalized the article.

References

  • Akoum A, Jolicoeur C & Boucher A 2000 Estradiol amplifies interleukin-1-induced monocyte chemotactic protein-1 expression by ectopic endometrial cells of women with endometriosis. Journal of Clinical Endocrinology and Metabolism 85 896904. (https://doi.org/10.1210/jcem.85.2.6348)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Banu SK, Lee J, Speights VO Jr, Starzinski-Powitz A & Arosh JA 2008 Cyclooxygenase-2 regulates survival, migration, and invasion of human endometriotic cells through multiple mechanisms. Endocrinology 149 11801189. (https://doi.org/10.1210/en.2007-1168)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Becker CM, Rohwer N, Funakoshi T, Cramer T, Bernhardt W, Birsner A, Folkman J & D’Amato RJ 2008 2-Methoxyestradiol inhibits hypoxia-inducible factor-1a and suppresses growth of lesions in a mouse model of endometriosis. American Journal of Pathology 172 534544. (https://doi.org/10.2353/ajpath.2008.061244)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bell SE, Mavila A, Salazar R, Bayless KJ, Kanagala S, Maxwell SA & Davis GE 2001 Differential gene expression during capillary morphogenesis in 3D collagen matrices: regulated expression of genes involved in basement membrane matrix assembly, cell cycle progression, cellular differentiation and G-protein signaling. Journal of Cell Science 114 27552773.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bruner-Tran KL, Eisenberg E, Yeaman GR, Anderson TA, McBean J & Osteen KG 2002 Steroid and cytokine regulation of matrix metalloproteinase expression in endometriosis and the establishment of experimental endometriosis in nude mice. Journal of Clinical Endocrinology and Metabolism 87 47824791. (https://doi.org/10.1210/jc.2002-020418)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Burney RO & Giudice LC 2012 Pathogenesis and pathophysiology of endometriosis. Fertility and Sterility 98 511519. (https://doi.org/10.1016/j.fertnstert.2012.06.029)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cea Soriano L, López-Garcia E, Schulze-Rath R & Garcia Rodríguez LA 2017 Incidence, treatment and recurrence of endometriosis in a UK-based population analysis using data from the Health Improvement Network and the Hospital Episode Statistics Database. European Journal of Contraception and Reproductive Health Care 22 334343. (https://doi.org/10.1080/13625187.2017.1374362)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chen PS, Chiu WT, Hsu PL, Lin SC, Peng IC, Wang CY & Tsai SJ 2020 Pathophysiological implications of hypoxia in human diseases. Journal of Biomedical Science 27 63. (https://doi.org/10.1186/s12929-020-00658-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cheong YC, Laird SM, Li TC, Shelton JB, Ledger WL & Cooke ID 2001 Peritoneal healing and adhesion formation/reformation. Human Reproduction Update 7 556566. (https://doi.org/10.1093/humupd/7.6.556)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Choi S, Shin H, Song H & Lim HJ 2014 Suppression of autophagic activation in the mouse uterus by estrogen and progesterone. Journal of Endocrinology 221 3950. (https://doi.org/10.1530/JOE-13-0449)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Choi HJ, Park MJ, Kim BS, Choi HJ, Joo B, Lee KS, Choi JH, Chung TW & Ha KT 2017 Transforming growth factor beta1 enhances adhesion of endometrial cells to mesothelium by regulating integrin expression. BMB Reports 50 429434. (https://doi.org/10.5483/bmbrep.2017.50.8.097)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chuang PC, Sun HS, Chen TM & Tsai SJ 2006 Prostaglandin E2 induces fibroblast growth factor 9 via EP3-dependent protein kinase Cdelta and Elk-1 signaling. Molecular and Cellular Biology 26 82818292. (https://doi.org/10.1128/MCB.00941-06)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chuang PC, Lin YJ, Wu MH, Wing LY, Shoji Y & Tsai SJ 2010 Inhibition of CD36-dependent phagocytosis by prostaglandin E2 contributes to the development of endometriosis. American Journal of Pathology 176 850860. (https://doi.org/10.2353/ajpath.2010.090551)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dai Y, Lin X, Xu W, Lin X, Huang Q, Shi L, Pan Y, Zhang Y, Zhu Y & Li C et al. 2019 MiR-210-3p protects endometriotic cells from oxidative stress-induced cell cycle arrest by targeting BARD1. Cell Death and Disease 10 144. (https://doi.org/10.1038/s41419-019-1395-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Delbandi AA, Mahmoudi M, Shervin A, Heidari S, Kolahdouz-Mohammadi R & Zarnani AH 2020 Evaluation of apoptosis and angiogenesis in ectopic and eutopic stromal cells of patients with endometriosis compared to non-endometriotic controls. BMC Women’s Health 20 3. (https://doi.org/10.1186/s12905-019-0865-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dyson MT, Roqueiro D, Monsivais D, Ercan CM, Pavone ME, Brooks DC, Kakinuma T, Ono M, Jafari N & Dai Y et al. 2014 Genome-wide DNA methylation analysis predicts an epigenetic switch for GATA factor expression in endometriosis. PLoS Genetics 10 e1004158. (https://doi.org/10.1371/journal.pgen.1004158)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fasciani A, D’Ambrogio G, Bocci G, Monti M, Genazzani AR & Artini PG 2000 High concentrations of the vascular endothelial growth factor and interleukin-8 in ovarian endometriomata. Molecular Human Reproduction 6 5054. (https://doi.org/10.1093/molehr/6.1.50)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fu JL, Hsiao KY, Lee HC, Li WN, Chang N, Wu MH & Tsai SJ 2018 Suppression of COUP-TFII upregulates angiogenin and promotes angiogenesis in endometriosis. Human Reproduction 33 15171527. (https://doi.org/10.1093/humrep/dey220)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fuchs Y & Steller H 2011 Programmed cell death in animal development and disease. Cell 147 742758. (https://doi.org/10.1016/j.cell.2011.10.033)

  • Gordon S 1998 The role of the macrophage in immune regulation. Research in Immunology 149 685688. (https://doi.org/10.1016/s0923-2494(9980039-x)

  • Gosden R & Spears N 1997 Programmed cell death in the reproductive system. British Medical Bulletin 53 644661. (https://doi.org/10.1093/oxfordjournals.bmb.a011636)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gou Y, Li X, Li P, Zhang H, Xu T, Wang H, Wang B, Ma X, Jiang X & Zhang Z 2019 Estrogen receptor beta upregulates CCL2 Via NF-kappaB signaling in endometriotic stromal cells and recruits macrophages to promote the pathogenesis of endometriosis. Human Reproduction 34 646658. (https://doi.org/10.1093/humrep/dez019)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Greaves E, Temp J, Esnal-Zufiurre A, Mechsner S, Horne AW & Saunders PT 2015 Estradiol is a critical mediator of macrophage-nerve cross talk in peritoneal endometriosis. American Journal of Pathology 185 22862297. (https://doi.org/10.1016/j.ajpath.2015.04.012)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Griffith JS, Liu YG, Tekmal RR, Binkley PA, Holden AE & Schenken RS 2010 Menstrual endometrial cells from women with endometriosis demonstrate increased adherence to peritoneal cells and increased expression of CD44 splice variants. Fertility and Sterility 93 17451749. (https://doi.org/10.1016/j.fertnstert.2008.12.012)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Guo SW 2009 Epigenetics of endometriosis. Molecular Human Reproduction 15 587607. (https://doi.org/10.1093/molehr/gap064)

  • Halme J, Hammond MG, Hulka JF, Raj SG & Talbert LM 1984 Retrograde menstruation in healthy women and in patients with endometriosis. Obstetrics and Gynecology 64 151154.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Han SJ, Jung SY, Wu SP, Hawkins SM, Park MJ, Kyo S, Qin J, Lydon JP, Tsai SY & Tsai MJ et al. 2015 Estrogen receptor beta modulates apoptosis complexes and the inflammasome to drive the pathogenesis of endometriosis. Cell 163 960974. (https://doi.org/10.1016/j.cell.2015.10.034)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Harada M, Suganuma N, Furuhashi M, Nagasaka T, Nakashima N, Kikkawa F, Tomoda Y & Furui K 1996 Detection of apoptosis in human endometriotic tissues. Molecular Human Reproduction 2 307315. (https://doi.org/10.1093/molehr/2.5.307)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hever A, Roth RB, Hevezi P, Marin ME, Acosta JA, Acosta H, Rojas J, Herrera R, Grigoriadis D & White E et al. 2007 Human endometriosis is associated with plasma cells and overexpression of B lymphocyte stimulator. PNAS 104 1245112456. (https://doi.org/10.1073/pnas.0703451104)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hsiao KY, Chang N, Lin SC, Li YH & Wu MH 2014 Inhibition of dual specificity phosphatase-2 by hypoxia promotes interleukin-8-mediated angiogenesis in endometriosis. Human Reproduction 29 27472755. (https://doi.org/10.1093/humrep/deu255)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hsiao KY, Wu MH, Chang N, Yang SH, Wu CW, Sun HS & Tsai SJ 2015 Coordination of AUF1 and miR-148a destabilizes DNA methyltransferase 1 mRNA under hypoxia in endometriosis. Molecular Human Reproduction 21 894904. (https://doi.org/10.1093/molehr/gav054)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hsiao KY, Chang N, Tsai JL, Lin SC, Tsai SJ & Wu MH 2017a Hypoxia-inhibited DUSP2 expression promotes IL-6/STAT3 signaling in endometriosis. American Journal of Reproductive Immunology 78. (https://doi.org/10.1111/aji.12690)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hsiao KY, Sun HS & Tsai SJ 2017b Circular RNA – new member of noncoding RNA with novel functions. Experimental Biology and Medicine 242 11361141. (https://doi.org/10.1177/1535370217708978)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hsu CY, Hsieh TH, Tsai CF, Tsai HP, Chen HS, Chang Y, Chuang HY, Lee JN, Hsu YL & Tsai EM 2014 miRNA-199a-5p regulates VEGFA in endometrial mesenchymal stem cells and contributes to the pathogenesis of endometriosis. Journal of Pathology 232 330343. (https://doi.org/10.1002/path.4295)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Huang JC, Papasakelariou C & Dawood MY 1996 Epidermal growth factor and basic fibroblast growth factor in peritoneal fluid of women with endometriosis. Fertility and Sterility 65 931934. (https://doi.org/10.1016/S0015-0282(1658263-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Imesch P, Samartzis EP, Schneider M, Fink D & Fedier A 2011 Inhibition of transcription, expression, and secretion of the vascular epithelial growth factor in human epithelial endometriotic cells by Romidepsin. Fertility and Sterility 95 15791583. (https://doi.org/10.1016/j.fertnstert.2010.12.058)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ishimaru T, Khan KN, Fujishita A, Kitajima M & Masuzaki H 2004 Hepatocyte growth factor may be involved in cellular changes to the peritoneal mesothelium adjacent to pelvic endometriosis. Fertility and Sterility 81 (Supplement 1) 810818. (https://doi.org/10.1016/j.fertnstert.2003.09.037)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Izawa M, Taniguchi F, Uegaki T, Takai E, Iwabe T, Terakawa N & Harada T 2011 Demethylation of a nonpromoter cytosine-phosphate-guanine island in the aromatase gene may cause the aberrant up-regulation in endometriotic tissues. Fertility and Sterility 95 3339. (https://doi.org/10.1016/j.fertnstert.2010.06.024)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jana S, Chatterjee K, Ray AK, DasMahapatra P & Swarnakar S 2016 Regulation of matrix metalloproteinase-2 activity by COX-2-PGE2-pAKT axis promotes angiogenesis in endometriosis. PLoS ONE 11 e0163540. (https://doi.org/10.1371/journal.pone.0163540)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jones RK, Searle RF & Bulmer JN 1998 Apoptosis and bcl-2 expression in normal human endometrium, endometriosis and adenomyosis. Human Reproduction 13 34963502. (https://doi.org/10.1093/humrep/13.12.3496)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Joshi N, Strakova Z, Yoo JY, Lessey B, Young S, Jeong JW & Fazleabas A 2016 Altered hippo signaling pathway in baboon and women with endometriosis. Reproductive Sciences 23 328a328a.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kawano Y, Nasu K, Li H, Tsuno A, Abe W, Takai N & Narahara H 2011 Application of the histone deacetylase inhibitors for the treatment of endometriosis: histone modifications as pathogenesis and novel therapeutic target. Human Reproduction 26 24862498. (https://doi.org/10.1093/humrep/der203)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Klemmt PAB, Carver JG, Koninckx P, McVeigh EJ & Mardon HJ 2007 Endometrial cells from women with endometriosis have increased adhesion and proliferative capacity in response to extracellular matrix components: towards a mechanistic model for endometriosis progression. Human Reproduction 22 31393147. (https://doi.org/10.1093/humrep/dem262)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kuessel L, Wenzl R, Proestling K, Balendran S, Pateisky P, Yotova G, Yerlikaya G, Streubel B & Husslein H 2017 Soluble VCAM-1/soluble ICAM-1 ratio is a promising biomarker for diagnosing endometriosis. Human Reproduction 32 770779. (https://doi.org/10.1093/humrep/dex028)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kupker W, Schultze-Mosgau A & Diedrich K 1998 Paracrine changes in the peritoneal environment of women with endometriosis. Human Reproduction Update 4 719723. (https://doi.org/10.1093/humupd/4.5.719)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lee HC, Lin SC, Wu MH & Tsai SJ 2019 Induction of pyruvate dehydrogenase kinase 1 by hypoxia alters cellular metabolism and inhibits apoptosis in endometriotic stromal cells. Reproductive Sciences 26 734744. (https://doi.org/10.1177/1933719118789513)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lessey BA, Castelbaum AJ, Sawin SW, Buck CA, Schinnar R, Bilker W & Strom BL 1994 Aberrant integrin expression in the endometrium of women with endometriosis. Journal of Clinical Endocrinology and Metabolism 79 643649. (https://doi.org/10.1210/jcem.79.2.7519194)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Li MQ, Wang Y, Chang KK, Meng YH, Liu LB, Mei J, Wang Y, Wang XQ, Jin LP & Li DJ 2014 CD4+Foxp3+ regulatory T cell differentiation mediated by endometrial stromal cell-derived TECK promotes the growth and invasion of endometriotic lesions. Cell Death and Disease 5 e1436. (https://doi.org/10.1038/cddis.2014.414)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liao WL, Lin SC, Sun HS & Tsai SJ 2014 Hypoxia-induced tumor malignancy and drug resistance: role of microRNAs. Biomarkers and Genomic Medicine 6 111. (https://doi.org/10.1016/j.bgm.2014.01.003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lin YJ, Lai MD, Lei HY & Wing LY 2006 Neutrophils and macrophages promote angiogenesis in the early stage of endometriosis in a mouse model. Endocrinology 147 12781286. (https://doi.org/10.1210/en.2005-0790)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lin SC, Wang CC, Wu MH, Yang SH, Li YH & Tsai SJ 2012 Hypoxia-induced microRNA-20a expression increases ERK phosphorylation and angiogenic gene expression in endometriotic stromal cells. Journal of Clinical Endocrinology and Metabolism 97 E1515E 1523. (https://doi.org/10.1210/jc.2012-1450)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lin SC, Li YH, Wu MH, Chang YF, Lee DK, Tsai SY, Tsai MJ & Tsai SJ 2014 Suppression of COUP-TFII by proinflammatory cytokines contributes to the pathogenesis of endometriosis. Journal of Clinical Endocrinology and Metabolism 99 E427E437. (https://doi.org/10.1210/jc.2013-3717)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lin SC, Lee HC, Hou PC, Fu JL, Wu MH & Tsai SJ 2017 Targeting hypoxia-mediated YAP1 nuclear translocation ameliorates pathogenesis of endometriosis without compromising maternal fertility. Journal of Pathology 242 476487. (https://doi.org/10.1002/path.4922)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lin X, Dai Y, Xu W, Shi L, Jin X, Li C, Zhou F, Pan Y, Zhang Y & Lin X et al. 2018 Hypoxia promotes ectopic adhesion ability of endometrial stromal cells via TGF-beta1/Smad signaling in endometriosis. Endocrinology 159 16301641. (https://doi.org/10.1210/en.2017-03227)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lin SC, Lee HC, Hsu CT, Huang YH, Li WN, Hsu PL, Wu MH & Tsai SJ 2019 Targeting anthrax toxin receptor 2 ameliorates endometriosis progression. Theranostics 9 620632. (https://doi.org/10.7150/thno.30655)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lindsten T, Ross AJ, King A, Zong WX, Rathmell JC, Shiels HA, Ulrich E, Waymire KG, Mahar P & Frauwirth K et al. 2000 The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Molecular Cell 6 13891399. (https://doi.org/10.1016/s1097-2765(0000136-2)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liu H, Zhang Z, Xiong W, Zhang L, Xiong Y, Li N, He H, Du Y & Liu Y 2017 Hypoxia-inducible factor-1alpha promotes endometrial stromal cells migration and invasion by upregulating autophagy in endometriosis. Reproduction 153 809820. (https://doi.org/10.1530/REP-16-0643)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liu H, Du Y, Zhang Z, Lv L, Xiong W, Zhang L, Li N, He H, Li Q & Liu Y 2018 Autophagy contributes to hypoxia-induced epithelial to mesenchymal transition of endometrial epithelial cells in endometriosis. Biology of Reproduction 99 968981. (https://doi.org/10.1093/biolre/ioy128)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liu H, Zhang Z, Xiong W, Zhang L, Du Y, Liu Y & Xiong X 2019 Long non-coding RNA MALAT1 mediates hypoxia-induced pro-survival autophagy of endometrial stromal cells in endometriosis. Journal of Cellular and Molecular Medicine 23 439452. (https://doi.org/10.1111/jcmm.13947)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Loh FH, Bongso A, Fong CY, Koh DR, Lee SH & Zhao HQ 1999 Effects of peritoneal macrophages from women with endometriosis on endometrial cellular proliferation in an in vitro coculture model. Fertility and Sterility 72 533538. (https://doi.org/10.1016/s0015-0282(9900292-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Maekawa R, Mihara Y, Sato S, Okada M, Tamura I, Shinagawa M, Shirafuta Y, Takagi H, Taketani T & Tamura H et al. 2019 Aberrant DNA methylation suppresses expression of estrogen receptor 1 (ESR1) in ovarian endometrioma. Journal of Ovarian Research 12 14. (https://doi.org/10.1186/s13048-019-0489-1)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • McLaren J, Prentice A, Charnock-Jones DS, Sharkey AM & Smith SK 1997 Immunolocalization of the apoptosis regulating proteins Bcl-2 and Bax in human endometrium and isolated peritoneal fluid macrophages in endometriosis. Human Reproduction 12 146152. (https://doi.org/10.1093/humrep/12.1.146)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mei J, Zhu XY, Jin LP, Duan ZL, Li DJ & Li MQ 2015 Estrogen promotes the survival of human secretory phase endometrial stromal cells via CXCL12/CXCR4 up-regulation-mediated autophagy inhibition. Human Reproduction 30 16771689. (https://doi.org/10.1093/humrep/dev100)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Moggio A, Pittatore G, Cassoni P, Marchino GL, Revelli A & Bussolati B 2012 Sorafenib inhibits growth, migration, and angiogenic potential of ectopic endometrial mesenchymal stem cells derived from patients with endometriosis. Fertility and Sterility 98 1521 .e2153 0.e2. (https://doi.org/10.1016/j.fertnstert.2012.08.003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Monteiro JB, Colon-Diaz M, Garcia M, Gutierrez S, Colon M, Seto E, Laboy J & Flores I 2014 Endometriosis is characterized by a distinct pattern of histone 3 and histone 4 lysine modifications. Reproductive Sciences 21 305318. (https://doi.org/10.1177/1933719113497267)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Mosser DM & Edwards JP 2008 Exploring the full spectrum of macrophage activation. Nature Reviews: Immunology 8 958969. (https://doi.org/10.1038/nri2448)

  • Pino M, Galleguillos C, Torres M, Sovino H, Fuentes A, Boric MA & Johnson MC 2009 Association between MMP1 and MMP9 activities and ICAM1 cleavage induced by tumor necrosis factor in stromal cell cultures from eutopic endometria of women with endometriosis. Reproduction 138 837847. (https://doi.org/10.1530/REP-09-0196)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Raiter-Tenenbaum A, Baranao RI, Etchepareborda JJ, Meresman GF & Rumi LS 1998 Functional and phenotypic alterations in peritoneal macrophages from patients with early and advanced endometriosis. Archives of Gynecology and Obstetrics 261 147157. (https://doi.org/10.1007/s004040050214)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Samartzis EP, Noske A, Samartzis N, Fink D & Imesch P 2013 The expression of histone deacetylase 1, but not other class I histone deacetylases, is significantly increased in endometriosis. Reproductive Sciences 20 14161422. (https://doi.org/10.1177/1933719113488450)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sampson JA 1927 Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue, into the venous circulation. American Journal of Pathology 3 93-U42.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sbracia M, Zupi E, Alo P, Manna C, Marconi D, Scarpellini F, Grasso JA, Di Tondo U & Romanini C 1997 Differential expression of IGF-I and IGF-II in eutopic and ectopic endometria of women with endometriosis and in women without endometriosis. American Journal of Reproductive Immunology 37 326329. (https://doi.org/10.1111/j.1600-0897.1997.tb00238.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Selam B, Kayisli UA, Akbas GE, Basar M & Arici A 2006 Regulation of Fas ligand expression by chemokine ligand 2 in human endometrial cells. Biology of Reproduction 75 203209. (https://doi.org/10.1095/biolreprod.105.045716)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Semenza GL 2007 Hypoxia-inducible factor 1 (HIF-1) pathway. Science’s Signal Transduction Knowledge Environment 2007 cm8. (https://doi.org/10.1126/stke.4072007cm8)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sharkey AM, Day K, McPherson A, Malik S, Licence D, Smith SK & Charnock-Jones DS 2000 Vascular endothelial growth factor expression in human endometrium is regulated by hypoxia. Journal of Clinical Endocrinology and Metabolism 85 402409. (https://doi.org/10.1210/jcem.85.1.6229)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Soliman AM, Yang H, Du EX, Kelley C & Winkel C 2016 The direct and indirect costs associated with endometriosis: a systematic literature review. Human Reproduction 31 712722. (https://doi.org/10.1093/humrep/dev335)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Song Y, Fu J, Zhou M, Xiao L, Feng X, Chen H & Huang W 2016 Activated hippo/yes-associated protein pathway promotes cell proliferation and anti-apoptosis in endometrial stromal cells of endometriosis. Journal of Clinical Endocrinology and Metabolism 101 15521561. (https://doi.org/10.1210/jc.2016-1120)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Soni UK, Chadchan SB, Kumar V, Ubba V, Khan MTA, Vinod BSV, Konwar R, Bora HK, Rath SK & Sharma S et al. 2019 A high level of TGF-B1 promotes endometriosis development via cell migration, adhesiveness, colonization, and invasivenessdagger. Biology of Reproduction 100 917938. (https://doi.org/10.1093/biolre/ioy242)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Sotnikova NY, Antsiferova YS, Posiseeva LV, Shishkov DN, Posiseev DV & Filippova ES 2010 Mechanisms regulating invasiveness and growth of endometriosis lesions in rat experimental model and in humans. Fertility and Sterility 93 27012705. (https://doi.org/10.1016/j.fertnstert.2009.11.024)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Stout AL, Steege JF, Dodson WC & Hughes CL 1991 Relationship of laparoscopic findings to self-report of pelvic pain. American Journal of Obstetrics and Gynecology 164 7379. (https://doi.org/10.1016/0002-9378(9190630-a)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tan CW, Lee YH, Tan HH, Lau MS, Choolani M, Griffith L & Chan JK 2014 CD26/DPPIV down-regulation in endometrial stromal cell migration in endometriosis. Fertility and Sterility 102 167 .e9177.e9. (https://doi.org/10.1016/j.fertnstert.2014.04.001)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Teague EM, Print CG & Hull ML 2010 The role of microRNAs in endometriosis and associated reproductive conditions. Human Reproduction Update 16 142165. (https://doi.org/10.1093/humupd/dmp034)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Tsai SJ, Wu MH, Chen HM, Chuang PC & Wing LY 2002 Fibroblast growth factor-9 is an endometrial stromal growth factor. Endocrinology 143 27152721. (https://doi.org/10.1210/endo.143.7.8900)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Veillat V, Sengers V, Metz CN, Roger T, Leboeuf M, Mailloux J & Akoum A 2012 Macrophage migration inhibitory factor is involved in a positive feedback loop increasing aromatase expression in endometriosis. American Journal of Pathology 181 917927. (https://doi.org/10.1016/j.ajpath.2012.05.018)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Vigano P, Gaffuri B, Somigliana E, Busacca M, Di Blasio AM & Vignali M 1998 Expression of intercellular adhesion molecule (ICAM)-1 mRNA and protein is enhanced in endometriosis versus endometrial stromal cells in culture. Molecular Human Reproduction 4 11501156. (https://doi.org/10.1093/molehr/4.12.1150)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Watanabe H, Kanzaki H, Narukawa S, Inoue T, Katsuragawa H, Kaneko Y & Mori T 1997 Bcl-2 and Fas expression in eutopic and ectopic human endometrium during the menstrual cycle in relation to endometrial cell apoptosis. American Journal of Obstetrics and Gynecology 176 360368. (https://doi.org/10.1016/s0002-9378(9770499-x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wing LY, Chuang PC, Wu MH, Chen HM & Tsai SJ 2003 Expression and mitogenic effect of fibroblast growth factor-9 in human endometriotic implant is regulated by aberrant production of estrogen. Journal of Clinical Endocrinology and Metabolism 88 55475554. (https://doi.org/10.1210/jc.2003-030597)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wing LY, Chen HM, Chuang PC, Wu MH & Tsai SJ 2005 The mammalian target of rapamycin-p70 ribosomal S6 kinase but not phosphatidylinositol 3-kinase-Akt signaling is responsible for fibroblast growth factor-9-induced cell proliferation. Journal of Biological Chemistry 280 1993719947. (https://doi.org/10.1074/jbc.M411865200)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wu M-H, Chuang PC, Chen SM, Lin CC & Tsai SJ 2002a Increased leptin expression in endometriosis cells is associated with endometrial stromal cell proliferation and leptin gene-upregulation. Molecular Human Reproduction 8 456464. (https://doi.org/10.1093/molehr/8.5.456)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wu MH, Sun HS, Lin CC, Hsiao KY, Chuang PC, Pan HA & Tsai SJ 2002b Distinct mechanisms regulate cyclooxygenase-1 and -2 in peritoneal macrophages of women with and without endometriosis. Molecular Human Reproduction 8 11031110. (https://doi.org/10.1093/molehr/8.12.1103)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wu MH, Shoji Y, Wu MC, Chuang PC, Lin CC, Huang MF & Tsai SJ 2005a Suppression of matrix metalloproteinase-9 by prostaglandin E(2) in peritoneal macrophage is associated with severity of endometriosis. American Journal of Pathology 167 10611069. (https://doi.org/10.1016/S0002-9440(1061195-9)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wu MH, Wang CA, Lin CC, Chen LC, Chang WC & Tsai SJ 2005b Distinct regulation of cyclooxygenase-2 by interleukin-1beta in normal and endometriotic stromal cells. Journal of Clinical Endocrinology and Metabolism 90 286295. (https://doi.org/10.1210/jc.2004-1612)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wu MH, Chen KF, Lin SC, Lgu CW & Tsai SJ 2007 Aberrant expression of leptin in human endometriotic stromal cells is induced by elevated levels of hypoxia inducible factor-1alpha. American Journal of Pathology 170 590598. (https://doi.org/10.2353/ajpath.2007.060477)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wu MH, Huang MF, Chang FM & Tsai SJ 2010 Leptin on peritoneal macrophages of patients with endometriosis. American Journal of Reproductive Immunology 63 214221. (https://doi.org/10.1111/j.1600-0897.2009.00779.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wu MH, Lin SC, Hsiao KY & Tsai SJ 2011 Hypoxia-inhibited dual-specificity phosphatase-2 expression in endometriotic cells regulates cyclooxygenase-2 expression. Journal of Pathology 225 390400. (https://doi.org/10.1002/path.2963)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wu MH, Lu CW, Chang FM & Tsai SJ 2012 Estrogen receptor expression affected by hypoxia inducible factor-1alpha in stromal cells from patients with endometriosis. Taiwanese Journal of Obstetrics and Gynecology 51 5054. (https://doi.org/10.1016/j.tjog.2012.01.010)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wu MH, Chuang PC, Lin YJ & Tsai SJ 2013 Suppression of annexin A2 by prostaglandin E(2) impairs phagocytic ability of peritoneal macrophages in women with endometriosis. Human Reproduction 28 10451053. (https://doi.org/10.1093/humrep/det003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Wu MH, Hsiao KY & Tsai SJ 2019 Hypoxia: the force of endometriosis. Journal of Obstetrics and Gynaecology Research 45 532541. (https://doi.org/10.1111/jog.13900)

  • Xu TX, Zhao SZ, Dong M & Yu XR 2016 Hypoxia responsive miR-210 promotes cell survival and autophagy of endometriotic cells in hypoxia. European Review for Medical and Pharmacological Sciences 20 399406.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Xue Q, Lin Z, Cheng YH, Huang CC, Marsh E, Yin P, Milad MP, Confino E, Reierstad S & Innes J et al. 2007a Promoter methylation regulates estrogen receptor 2 in human endometrium and endometriosis. Biology of Reproduction 77 681687. (https://doi.org/10.1095/biolreprod.107.061804)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Xue Q, Lin Z, Yin P, Milad MP, Cheng YH, Confino E, Reierstad S & Bulun SE 2007b Transcriptional activation of steroidogenic factor-1 by hypomethylation of the 5’ CpG island in endometriosis. Journal of Clinical Endocrinology and Metabolism 92 32613267. (https://doi.org/10.1210/jc.2007-0494)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Young VJ, Ahmad SF, Brown JK, Duncan WC & Horne AW 2016 ID2 mediates the transforming growth factor-beta1-induced Warburg-like effect seen in the peritoneum of women with endometriosis. Molecular Human Reproduction 22 648654. (https://doi.org/10.1093/molehr/gaw045)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Yu L, Chen Y & Tooze SA 2018 Autophagy pathway: cellular and molecular mechanisms. Autophagy 14 207215. (https://doi.org/10.1080/15548627.2017.1378838)

 

  • Collapse
  • Expand
  • Figure 1

    Schematic drawing shows the pathophysiological effects of hypoxia during the development and progression of endometriosis.

  • Figure 2

    Hypoxia-regulated signaling pathways leading to angiogenesis in endometriosis. Adapted with permission from Fig. 2 from the article ‘Hypoxia: The force of Endometriosis’ published in ‘J. Obstet. Gynaecol. Res. Vol. 45, No. 3: 532–541, March 2019’.

  • Figure 3

    Involvement of hypoxia in epigenetic regulation in the pathogenesis of endometriosis.

  • Akoum A, Jolicoeur C & Boucher A 2000 Estradiol amplifies interleukin-1-induced monocyte chemotactic protein-1 expression by ectopic endometrial cells of women with endometriosis. Journal of Clinical Endocrinology and Metabolism 85 896904. (https://doi.org/10.1210/jcem.85.2.6348)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Banu SK, Lee J, Speights VO Jr, Starzinski-Powitz A & Arosh JA 2008 Cyclooxygenase-2 regulates survival, migration, and invasion of human endometriotic cells through multiple mechanisms. Endocrinology 149 11801189. (https://doi.org/10.1210/en.2007-1168)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Becker CM, Rohwer N, Funakoshi T, Cramer T, Bernhardt W, Birsner A, Folkman J & D’Amato RJ 2008 2-Methoxyestradiol inhibits hypoxia-inducible factor-1a and suppresses growth of lesions in a mouse model of endometriosis. American Journal of Pathology 172 534544. (https://doi.org/10.2353/ajpath.2008.061244)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bell SE, Mavila A, Salazar R, Bayless KJ, Kanagala S, Maxwell SA & Davis GE 2001 Differential gene expression during capillary morphogenesis in 3D collagen matrices: regulated expression of genes involved in basement membrane matrix assembly, cell cycle progression, cellular differentiation and G-protein signaling. Journal of Cell Science 114 27552773.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bruner-Tran KL, Eisenberg E, Yeaman GR, Anderson TA, McBean J & Osteen KG 2002 Steroid and cytokine regulation of matrix metalloproteinase expression in endometriosis and the establishment of experimental endometriosis in nude mice. Journal of Clinical Endocrinology and Metabolism 87 47824791. (https://doi.org/10.1210/jc.2002-020418)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Burney RO & Giudice LC 2012 Pathogenesis and pathophysiology of endometriosis. Fertility and Sterility 98 511519. (https://doi.org/10.1016/j.fertnstert.2012.06.029)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cea Soriano L, López-Garcia E, Schulze-Rath R & Garcia Rodríguez LA 2017 Incidence, treatment and recurrence of endometriosis in a UK-based population analysis using data from the Health Improvement Network and the Hospital Episode Statistics Database. European Journal of Contraception and Reproductive Health Care 22 334343. (https://doi.org/10.1080/13625187.2017.1374362)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chen PS, Chiu WT, Hsu PL, Lin SC, Peng IC, Wang CY & Tsai SJ 2020 Pathophysiological implications of hypoxia in human diseases. Journal of Biomedical Science 27 63. (https://doi.org/10.1186/s12929-020-00658-7)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cheong YC, Laird SM, Li TC, Shelton JB, Ledger WL & Cooke ID 2001 Peritoneal healing and adhesion formation/reformation. Human Reproduction Update 7 556566. (https://doi.org/10.1093/humupd/7.6.556)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Choi S, Shin H, Song H & Lim HJ 2014 Suppression of autophagic activation in the mouse uterus by estrogen and progesterone. Journal of Endocrinology 221 3950. (https://doi.org/10.1530/JOE-13-0449)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Choi HJ, Park MJ, Kim BS, Choi HJ, Joo B, Lee KS, Choi JH, Chung TW & Ha KT 2017 Transforming growth factor beta1 enhances adhesion of endometrial cells to mesothelium by regulating integrin expression. BMB Reports 50 429434. (https://doi.org/10.5483/bmbrep.2017.50.8.097)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chuang PC, Sun HS, Chen TM & Tsai SJ 2006 Prostaglandin E2 induces fibroblast growth factor 9 via EP3-dependent protein kinase Cdelta and Elk-1 signaling. Molecular and Cellular Biology 26 82818292. (https://doi.org/10.1128/MCB.00941-06)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chuang PC, Lin YJ, Wu MH, Wing LY, Shoji Y & Tsai SJ 2010 Inhibition of CD36-dependent phagocytosis by prostaglandin E2 contributes to the development of endometriosis. American Journal of Pathology 176 850860. (https://doi.org/10.2353/ajpath.2010.090551)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dai Y, Lin X, Xu W, Lin X, Huang Q, Shi L, Pan Y, Zhang Y, Zhu Y & Li C et al. 2019 MiR-210-3p protects endometriotic cells from oxidative stress-induced cell cycle arrest by targeting BARD1. Cell Death and Disease 10 144. (https://doi.org/10.1038/s41419-019-1395-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Delbandi AA, Mahmoudi M, Shervin A, Heidari S, Kolahdouz-Mohammadi R & Zarnani AH 2020 Evaluation of apoptosis and angiogenesis in ectopic and eutopic stromal cells of patients with endometriosis compared to non-endometriotic controls. BMC Women’s Health 20 3. (https://doi.org/10.1186/s12905-019-0865-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Dyson MT, Roqueiro D, Monsivais D, Ercan CM, Pavone ME, Brooks DC, Kakinuma T, Ono M, Jafari N & Dai Y et al. 2014 Genome-wide DNA methylation analysis predicts an epigenetic switch for GATA factor expression in endometriosis. PLoS Genetics 10 e1004158. (https://doi.org/10.1371/journal.pgen.1004158)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fasciani A, D’Ambrogio G, Bocci G, Monti M, Genazzani AR & Artini PG 2000 High concentrations of the vascular endothelial growth factor and interleukin-8 in ovarian endometriomata. Molecular Human Reproduction 6 5054. (https://doi.org/10.1093/molehr/6.1.50)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fu JL, Hsiao KY, Lee HC, Li WN, Chang N, Wu MH & Tsai SJ 2018 Suppression of COUP-TFII upregulates angiogenin and promotes angiogenesis in endometriosis. Human Reproduction 33 15171527. (https://doi.org/10.1093/humrep/dey220)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Fuchs Y & Steller H 2011 Programmed cell death in animal development and disease. Cell 147 742758. (https://doi.org/10.1016/j.cell.2011.10.033)

  • Gordon S 1998 The role of the macrophage in immune regulation. Research in Immunology 149 685688. (https://doi.org/10.1016/s0923-2494(9980039-x)

  • Gosden R & Spears N 1997 Programmed cell death in the reproductive system. British Medical Bulletin 53 644661. (https://doi.org/10.1093/oxfordjournals.bmb.a011636)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Gou Y, Li X, Li P, Zhang H, Xu T, Wang H, Wang B, Ma X, Jiang X & Zhang Z 2019 Estrogen receptor beta upregulates CCL2 Via NF-kappaB signaling in endometriotic stromal cells and recruits macrophages to promote the pathogenesis of endometriosis. Human Reproduction 34 646658. (https://doi.org/10.1093/humrep/dez019)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Greaves E, Temp J, Esnal-Zufiurre A, Mechsner S, Horne AW & Saunders PT 2015 Estradiol is a critical mediator of macrophage-nerve cross talk in peritoneal endometriosis. American Journal of Pathology 185 22862297. (https://doi.org/10.1016/j.ajpath.2015.04.012)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Griffith JS, Liu YG, Tekmal RR, Binkley PA, Holden AE & Schenken RS 2010 Menstrual endometrial cells from women with endometriosis demonstrate increased adherence to peritoneal cells and increased expression of CD44 splice variants. Fertility and Sterility 93 17451749. (https://doi.org/10.1016/j.fertnstert.2008.12.012)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Guo SW 2009 Epigenetics of endometriosis. Molecular Human Reproduction 15 587607. (https://doi.org/10.1093/molehr/gap064)

  • Halme J, Hammond MG, Hulka JF, Raj SG & Talbert LM 1984 Retrograde menstruation in healthy women and in patients with endometriosis. Obstetrics and Gynecology 64 151154.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Han SJ, Jung SY, Wu SP, Hawkins SM, Park MJ, Kyo S, Qin J, Lydon JP, Tsai SY & Tsai MJ et al. 2015 Estrogen receptor beta modulates apoptosis complexes and the inflammasome to drive the pathogenesis of endometriosis. Cell 163 960974. (https://doi.org/10.1016/j.cell.2015.10.034)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Harada M, Suganuma N, Furuhashi M, Nagasaka T, Nakashima N, Kikkawa F, Tomoda Y & Furui K 1996 Detection of apoptosis in human endometriotic tissues. Molecular Human Reproduction 2 307315. (https://doi.org/10.1093/molehr/2.5.307)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hever A, Roth RB, Hevezi P, Marin ME, Acosta JA, Acosta H, Rojas J, Herrera R, Grigoriadis D & White E et al. 2007 Human endometriosis is associated with plasma cells and overexpression of B lymphocyte stimulator. PNAS 104 1245112456. (https://doi.org/10.1073/pnas.0703451104)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hsiao KY, Chang N, Lin SC, Li YH & Wu MH 2014 Inhibition of dual specificity phosphatase-2 by hypoxia promotes interleukin-8-mediated angiogenesis in endometriosis. Human Reproduction 29 27472755. (https://doi.org/10.1093/humrep/deu255)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hsiao KY, Wu MH, Chang N, Yang SH, Wu CW, Sun HS & Tsai SJ 2015 Coordination of AUF1 and miR-148a destabilizes DNA methyltransferase 1 mRNA under hypoxia in endometriosis. Molecular Human Reproduction 21 894904. (https://doi.org/10.1093/molehr/gav054)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hsiao KY, Chang N, Tsai JL, Lin SC, Tsai SJ & Wu MH 2017a Hypoxia-inhibited DUSP2 expression promotes IL-6/STAT3 signaling in endometriosis. American Journal of Reproductive Immunology 78. (https://doi.org/10.1111/aji.12690)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hsiao KY, Sun HS & Tsai SJ 2017b Circular RNA – new member of noncoding RNA with novel functions. Experimental Biology and Medicine 242 11361141. (https://doi.org/10.1177/1535370217708978)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Hsu CY, Hsieh TH, Tsai CF, Tsai HP, Chen HS, Chang Y, Chuang HY, Lee JN, Hsu YL & Tsai EM 2014 miRNA-199a-5p regulates VEGFA in endometrial mesenchymal stem cells and contributes to the pathogenesis of endometriosis. Journal of Pathology 232 330343. (https://doi.org/10.1002/path.4295)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Huang JC, Papasakelariou C & Dawood MY 1996 Epidermal growth factor and basic fibroblast growth factor in peritoneal fluid of women with endometriosis. Fertility and Sterility 65 931934. (https://doi.org/10.1016/S0015-0282(1658263-6)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Imesch P, Samartzis EP, Schneider M, Fink D & Fedier A 2011 Inhibition of transcription, expression, and secretion of the vascular epithelial growth factor in human epithelial endometriotic cells by Romidepsin. Fertility and Sterility 95 15791583. (https://doi.org/10.1016/j.fertnstert.2010.12.058)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Ishimaru T, Khan KN, Fujishita A, Kitajima M & Masuzaki H 2004 Hepatocyte growth factor may be involved in cellular changes to the peritoneal mesothelium adjacent to pelvic endometriosis. Fertility and Sterility 81 (Supplement 1) 810818. (https://doi.org/10.1016/j.fertnstert.2003.09.037)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Izawa M, Taniguchi F, Uegaki T, Takai E, Iwabe T, Terakawa N & Harada T 2011 Demethylation of a nonpromoter cytosine-phosphate-guanine island in the aromatase gene may cause the aberrant up-regulation in endometriotic tissues. Fertility and Sterility 95 3339. (https://doi.org/10.1016/j.fertnstert.2010.06.024)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jana S, Chatterjee K, Ray AK, DasMahapatra P & Swarnakar S 2016 Regulation of matrix metalloproteinase-2 activity by COX-2-PGE2-pAKT axis promotes angiogenesis in endometriosis. PLoS ONE 11 e0163540. (https://doi.org/10.1371/journal.pone.0163540)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Jones RK, Searle RF & Bulmer JN 1998 Apoptosis and bcl-2 expression in normal human endometrium, endometriosis and adenomyosis. Human Reproduction 13 34963502. (https://doi.org/10.1093/humrep/13.12.3496)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Joshi N, Strakova Z, Yoo JY, Lessey B, Young S, Jeong JW & Fazleabas A 2016 Altered hippo signaling pathway in baboon and women with endometriosis. Reproductive Sciences 23 328a328a.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kawano Y, Nasu K, Li H, Tsuno A, Abe W, Takai N & Narahara H 2011 Application of the histone deacetylase inhibitors for the treatment of endometriosis: histone modifications as pathogenesis and novel therapeutic target. Human Reproduction 26 24862498. (https://doi.org/10.1093/humrep/der203)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Klemmt PAB, Carver JG, Koninckx P, McVeigh EJ & Mardon HJ 2007 Endometrial cells from women with endometriosis have increased adhesion and proliferative capacity in response to extracellular matrix components: towards a mechanistic model for endometriosis progression. Human Reproduction 22 31393147. (https://doi.org/10.1093/humrep/dem262)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kuessel L, Wenzl R, Proestling K, Balendran S, Pateisky P, Yotova G, Yerlikaya G, Streubel B & Husslein H 2017 Soluble VCAM-1/soluble ICAM-1 ratio is a promising biomarker for diagnosing endometriosis. Human Reproduction 32 770779. (https://doi.org/10.1093/humrep/dex028)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Kupker W, Schultze-Mosgau A & Diedrich K 1998 Paracrine changes in the peritoneal environment of women with endometriosis. Human Reproduction Update 4 719723. (https://doi.org/10.1093/humupd/4.5.719)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lee HC, Lin SC, Wu MH & Tsai SJ 2019 Induction of pyruvate dehydrogenase kinase 1 by hypoxia alters cellular metabolism and inhibits apoptosis in endometriotic stromal cells. Reproductive Sciences 26 734744. (https://doi.org/10.1177/1933719118789513)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lessey BA, Castelbaum AJ, Sawin SW, Buck CA, Schinnar R, Bilker W & Strom BL 1994 Aberrant integrin expression in the endometrium of women with endometriosis. Journal of Clinical Endocrinology and Metabolism 79 643649. (https://doi.org/10.1210/jcem.79.2.7519194)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Li MQ, Wang Y, Chang KK, Meng YH, Liu LB, Mei J, Wang Y, Wang XQ, Jin LP & Li DJ 2014 CD4+Foxp3+ regulatory T cell differentiation mediated by endometrial stromal cell-derived TECK promotes the growth and invasion of endometriotic lesions. Cell Death and Disease 5 e1436. (https://doi.org/10.1038/cddis.2014.414)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liao WL, Lin SC, Sun HS & Tsai SJ 2014 Hypoxia-induced tumor malignancy and drug resistance: role of microRNAs. Biomarkers and Genomic Medicine 6 111. (https://doi.org/10.1016/j.bgm.2014.01.003)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lin YJ, Lai MD, Lei HY & Wing LY 2006 Neutrophils and macrophages promote angiogenesis in the early stage of endometriosis in a mouse model. Endocrinology 147 12781286. (https://doi.org/10.1210/en.2005-0790)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lin SC, Wang CC, Wu MH, Yang SH, Li YH & Tsai SJ 2012 Hypoxia-induced microRNA-20a expression increases ERK phosphorylation and angiogenic gene expression in endometriotic stromal cells. Journal of Clinical Endocrinology and Metabolism 97 E1515E 1523. (https://doi.org/10.1210/jc.2012-1450)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lin SC, Li YH, Wu MH, Chang YF, Lee DK, Tsai SY, Tsai MJ & Tsai SJ 2014 Suppression of COUP-TFII by proinflammatory cytokines contributes to the pathogenesis of endometriosis. Journal of Clinical Endocrinology and Metabolism 99 E427E437. (https://doi.org/10.1210/jc.2013-3717)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lin SC, Lee HC, Hou PC, Fu JL, Wu MH & Tsai SJ 2017 Targeting hypoxia-mediated YAP1 nuclear translocation ameliorates pathogenesis of endometriosis without compromising maternal fertility. Journal of Pathology 242 476487. (https://doi.org/10.1002/path.4922)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lin X, Dai Y, Xu W, Shi L, Jin X, Li C, Zhou F, Pan Y, Zhang Y & Lin X et al. 2018 Hypoxia promotes ectopic adhesion ability of endometrial stromal cells via TGF-beta1/Smad signaling in endometriosis. Endocrinology 159 16301641. (https://doi.org/10.1210/en.2017-03227)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lin SC, Lee HC, Hsu CT, Huang YH, Li WN, Hsu PL, Wu MH & Tsai SJ 2019 Targeting anthrax toxin receptor 2 ameliorates endometriosis progression. Theranostics 9 620632. (https://doi.org/10.7150/thno.30655)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lindsten T, Ross AJ, King A, Zong WX, Rathmell JC, Shiels HA, Ulrich E, Waymire KG, Mahar P & Frauwirth K et al. 2000 The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Molecular Cell 6 13891399. (https://doi.org/10.1016/s1097-2765(0000136-2)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liu H, Zhang Z, Xiong W, Zhang L, Xiong Y, Li N, He H, Du Y & Liu Y 2017 Hypoxia-inducible factor-1alpha promotes endometrial stromal cells migration and invasion by upregulating autophagy in endometriosis. Reproduction 153 809820. (https://doi.org/10.1530/REP-16-0643)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liu H, Du Y, Zhang Z, Lv L, Xiong W, Zhang L, Li N, He H, Li Q & Liu Y 2018 Autophagy contributes to hypoxia-induced epithelial to mesenchymal transition of endometrial epithelial cells in endometriosis. Biology of Reproduction 99 968981. (https://doi.org/10.1093/biolre/ioy128)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Liu H, Zhang Z, Xiong W, Zhang L