Abstract
In brief
There is a pregnancy-induced vasodilation of blood vessels, which is known to have a protective effect on cardiovascular function and can be maintained postpartum. This review outlines the cardiovascular changes that occur in a healthy human and rodent pregnancy, as well as different pathways that are activated by angiotensin II and relaxin that result in blood vessel dilation.
Abstract
During pregnancy, systemic and uteroplacental blood flow increase to ensure an adequate blood supply that carries oxygen and nutrients from the mother to the fetus. This results in changes to the function of the maternal cardiovascular system. There is also a pregnancy-induced vasodilation of blood vessels, which is known to have a protective effect on cardiovascular health/function. Additionally, there is evidence that the effects of maternal vascular vasodilation are maintained post-partum, which may reduce the risk of developing high blood pressure in the next pregnancy and reduce cardiovascular risk later in life. At both non-pregnant and pregnant stages, vascular endothelial cells produce a number of vasodilators and vasoconstrictors, which transduce signals to the contractile vascular smooth muscle cells to control the dilation and constriction of blood vessels. These vascular cells are also targets of other vasoactive factors, including angiotensin II (Ang II) and relaxin. The binding of Ang II to its receptors activates different pathways to regulate the blood vessel vasoconstriction/vasodilation, and relaxin can interact with some of these pathways to induce vasodilation. Based on the available literature, this review outlines the cardiovascular changes that occur in a healthy human pregnancy, supplemented by studies in rodents. A specific focus is placed on vasodilation of blood vessels during pregnancy; the role of endothelial cells and endothelium-derived vasodilators will also be discussed. Additionally, different pathways that are activated by Ang II and relaxin that result in blood vessel dilation will also be reviewed.
Introduction
Cardiac output is represented by heart beats per minute (heart rate) and the volume of blood pumped into the aorta from the left ventricle per minute (stroke volume) (Hunter & Robson 1992). In a healthy human pregnancy, both local uterine blood flow and cardiac output increase. This ensures an adequate supply of oxygen and nutrients from the mother to the fetus (Hunter & Robson 1992, Melchiorre et al. 2012). The elevation of cardiac output usually starts from the 5th week of gestation, reaches maximum value at 20–32 weeks’ of gestation (heart rate nearly 45% higher than pre-pregnancy value), and returns to pre-pregnancy levels 2 weeks post-partum (Hunter & Robson 1992, Meah et al. 2016). Simultaneously, alterations in maternal vascular function occur to accommodate increased blood flow.
Vasodilation or relaxation of blood vessels, which occurs from early to mid-gestation, is known to be an adaptation to protect the maternal cardiovascular system throughout pregnancy, as it maintains a normal or decreased pressure when the volume of blood being pumped from the heart into these vessels increases (Guyton 1981, Hunter & Robson 1992). Specifically, despite an increase in plasma volume by 6 weeks of gestation, a decrease in both peripheral and renal vascular resistance results in decreased blood pressure and increased renal flow (West et al. 2016). This rise in plasma volume and decrease in vascular resistance is also likely accounted for in part by arterial underfilling with 85% of the volume residing in the venous circulation (Davison 1984). These adaptions help reduce the risk of developing hypertensive complications such as preeclampsia (Conrad 2011, Osol et al. 2019), which predisposes women to a 3.5-fold, 2.1-fold, and 1.8-fold higher risk for developing hypertension, coronary heart disease, and stroke, later in life (Bellamy et al. 2007, Carpenter 2007, Lykke et al. 2009, Yinon et al. 2010, Naderi et al. 2017, Thilaganathan & Kalafat 2019). Findings in both human and animal studies have also suggested that blood vessel dilation is maintained post-partum, which may decrease the risk of developing hypertension in subsequent pregnancies and lower the risk of developing cardiovascular disease later in life (Gunderson et al. 2008, van der Heijden et al. 2009, Morris et al. 2015, 2020).
This literature review will cover vasculature changes, specifically blood vessel vasodilation during pregnancy and post-partum in a normal pregnancy in both human and rodents. In addition, it will also discuss the role of angiotensin II (Ang II) and relaxin in vascular adaptation during pregnancy, different pathways that are activated by the binding of Ang II to its receptors, and the potential interaction between relaxin and Ang II receptors. Changes to the pathways mentioned earlier when there is endothelial dysfunction, similar to that which may occur in preeclampsia, will also be reviewed.
Materials and methods
A literature search for primary peer-reviewed papers that investigate maternal blood vessel dilation during pregnancy and its mechanisms was conducted in PubMed and Web of Sciences using search terms ‘pregnancy vasodilation’, ‘vascular endothelial cells’, ‘vascular smooth muscle cells’, ‘angiotensin II’, and ‘relaxin’ up to June 2022. There were 193 papers retrieved based on the search terms. Papers that are not in English and were not available in full text were excluded. The final number of papers retained was 136.
Results and discussion
Vasculature changes in a healthy human pregnancy
Changes in mean arterial pressure
Mean arterial pressure (MAP, mmHg) is an indicator of the average pressure in blood vessels during one cardiac cycle (Cnossen et al. 2008). MAP is calculated using the formula (2 diastolic pressure + systolic pressure)/3, in which diastolic pressure is the blood pressure measured when the heart relaxes, and systolic pressure is measured when the heart contracts (Cnossen et al. 2008). Most studies of healthy women (non-smokers, have normal BMI with no history of blood pressure-related disorders and/or usage of hypertensive medication) in their first pregnancy (primiparous women) reported a reduction in MAP (by a maximum of 2–3.4 mmHg of the non-pregnant level) in the first two trimesters of pregnancy and an increase to pre-pregnancy value (79–83 mmHg) from the third trimester until term (Kametas et al. 2001, Simmons et al. 2002, Morris et al. 2014, Melchiorre et al. 2016). In the second or third pregnancy, MAP values within each trimester are lower compared to primiparous women (Bernstein et al. 2005). Moreover, there was a negative correlation (r = −0.31) between the interval between pregnancies (11–67 months) and the degree of changes in MAP throughout a pregnancy, suggesting that a shorter interval between pregnancies is associated with a greater decrease in MAP (Bernstein et al. 2005). However, MAP always reaches the highest value within the third trimester, compared to other trimesters, regardless of the number of previous pregnancies (Bernstein et al. 2005). On the other hand, other studies have reported a further decrease in blood pressure at post-partum in both primiparous women and women who had two or more pregnancies (Gunderson et al. 2008, Morris et al. 2015). Specifically, primiparous women had decreased MAP, by 4.8 mmHg, at 14 months post-partum (Morris et al. 2015), or decreased mean adjusted diastolic and systolic blood pressure (by 1.50 and 2.06 mmHg, respectively) at up to 20 years post-partum, compared to pre-pregnancy values (Gunderson et al. 2008). Similarly, at 20 years post-partum, women who had two or more pregnancies had a further decrease in diastolic and systolic blood pressure (1.29 mmHg and 1.89 mmHg, respectively), compared to non-pregnant women (Gunderson et al. 2008). However, both studies mainly focused on Caucasian or women of colour; hence, the results may not be generalised for all ethnic minorities (Gunderson et al. 2008, Morris et al. 2015). Additionally, these studies did not investigate changes in blood pressure measures during pregnancy.
Similar to changes observed in humans, rodent studies have also reported a decrease in MAP during pregnancy (Barron et al. 2010, Mirabito et al. 2014, Mirabito Colafella et al. 2017). In pregnant mice, MAP gradually decreased from early gestation and reached the lowest value (−6 ± 2 mmHg) at gestational day 9 (Mirabito et al. 2014, Mirabito Colafella et al. 2017), which is an adaptation to the pregnancy-induced increase in heart rate (+60 b.p.m. compared to pre-pregnancy value) (Mirabito Colafella et al. 2017). Both heart rate and MAP then increased to pre-pregnancy values from day 19–20 of gestation (late gestation) (Mirabito et al. 2014, Mirabito Colafella et al. 2017), and this value of MAP was also confirmed at 2 weeks post-partum (88 ± 2 mmHg) (Mirabito et al. 2014).
Changes in uterine arterial function
Besides changes in MAP, uterine artery function is also altered during pregnancy, as the cardiac output and uteroplacental circulation increase (Bernstein et al. 2002, Osol & Moore 2014). As expected, elevated uterine artery mean flow velocity, that is, the rate by which blood travelled through the blood vessels per unit of time, has been reported throughout pregnancy (Palmer et al. 1992, Dickey & Hower 1995, Bernstein et al. 2002, Rigano et al. 2010). In order to compensate for this, the average uterine artery diameter increases from mid-gestation (2.6 mm) to late pregnancy (3.0 mm) (Palmer et al. 1992, Rigano et al. 2010). Uterine artery resistance index (Dickey & Hower 1995) and uterine artery pulsatility index also decrease when examined in early pregnancy (Bernstein et al. 2002, Ogueh et al. 2011). However, it should be noted that pregnancy-induced changes in the uterine circulation and its resistance is a result of far more than remodelling and vascular reactivity changes of the uterine artery itself. For instance, there was an increase by approximately 2-fold in the diameter of arcuate arteries (smaller branches of uterine arteries) and radial arteries (smaller branches of arcuate arteries) in normal pregnancies, from 6.1 to 20.5 weeks of gestation (Allerkamp et al. 2021).
In agreement with human studies, examination of rodent uterine arteries has also reported maternal blood vessel dilation as an adaptation to pregnancy (Cooke & Davidge 2003, van der Heijden et al. 2009, Barron et al. 2010, Vodstrcil et al. 2012). In late pregnancy, rats (van der Heijden et al. 2009, Barron et al. 2010) and mice (Cooke & Davidge 2003) have an increase in arterial vasodilation within the uterus compared to non-pregnant controls, with a 35% increase in diameter of radial arteries (Barron et al. 2010), and a 20% increase in the methacholine-induced vasodilation response of the uterine artery when measured using wire myography (Cooke & Davidge 2003). The enlargement in uterine artery diameter has also been reported in pregnant animals at 1 week (Morris et al. 2020) and 10 days (van der Heijden et al. 2009) post-partum, which may help maintain a high uterine blood flow and, hence, may be advantageous for subsequent pregnancies (van der Heijden et al. 2009).
Changes in mesenteric function
Similar to the observations in uterine arteries, mesenteric arteries of late-pregnant mice (day 17–18) show increased sensitivity towards vasodilators (e.g. methacholine) (Cooke & Davidge 2003) and a decreased sensitivity towards vasoconstrictors (e.g. Ang II) by half the non-pregnant control (Marshall et al. 2016). Additionally, in mesenteric arteries of late-pregnant rats, there was a decrease in myogenic reactivity, represented by the decreased contraction of smooth muscle cells in response to induced intraluminal flow and pressure (Meyer et al. 1997). This reduction in myogenic reactivity was associated with a decrease in the shear stress that blood vessels experience during pregnancy (−4% in late-pregnant rats vs +54.7% in non-pregnant control) likely a protective mechanism of the maternal vasculature system (Meyer et al. 1997). Interestingly, there is also evidence for maintenance of pregnancy-induced vasodilation effect, as the mesenteric artery distensibility (i.e. the ability to dilate and constrict passively in response to changes in pressure) in pregnant rats was shown to increase considerably throughout pregnancy and was approximately 30% higher than in non-pregnant controls at 4 weeks post-partum (Morris et al. 2020).
Changes in renal arterial function
As previously mentioned, it is generally accepted that renal vascular resistance decreases to accommodate for increased renal blood flow during pregnancy. Indeed, using the renal para-aminohippurate (PAH) clearance method, most human studies reported a significant increase in maternal renal blood flow from as early as the 6th week up to week 36 of gestation, reflecting a reduction in renal vascular resistance (Sims & Krantz 1958, Dunlop 1981, Sturgiss et al. 1996, Chapman et al. 1998). Renal vascular resistance (calculated using MAP and renal blood flow) was shown to decrease concurrently (Chapman et al. 1998). Interestingly, increased renal blood flow was even found at up to 25 weeks post-partum, compared to non-pregnant controls (Sims & Krantz 1958). In contrast, the investigation of renal arterial resistive index (RI) using Doppler-based measurement reported either no change in RI throughout gestation (Dib et al. 2003) or a significant increase in RI in gestational weeks’ 16–36 (Kurjak et al. 1992, Ogueh et al. 2011). RI is calculated using systolic and diastolic velocities and, therefore, might also be influenced by other central haemodynamic parameters rather than the renal vascular resistance itself. As a result, differences in the examination methods/measures, as well as examination intervals and number of samples, are potential explanations for the conflicting results. Similar to the results found in human studies, pregnant rats either had increased renal blood flow at mid-gestation and late gestation (Matthews & Taylor 1960) or no change in renal blood flow at early gestation and late gestation (Davison & Lindheimer 1980), represented by increased PAH clearance. However, the former study was done in anaesthetised rats, while the latter was done in unanaesthetised rats. Meanwhile, pregnant rats at mid-gestation were reported to have a significant decrease in myogenic reactivity of small renal arteries compared to non-pregnant control, supporting the potential vasodilation effect of pregnancy on the renal vascular function (Gandley et al. 2001, Novak et al. 2001).
A summary of vasculature changes in healthy human and rodent pregnancy is shown in Table 1. Although this review discusses the function and biochemical aspects of isolated vessels from pregnant humans and animals, it should be noted that there are remarkable differences in blood vessel behaviour between and within different organs; hence, it is important for future studies to investigate and provide a better understanding of the pregnancy-specific vasodilation effects on the maternal vasculature system as a whole. Additionally, although rodent studies are the most common, other studies on maternal blood vessel vasodilation during gestation have also been performed in larger animal models such as rabbits, sheep, and guinea pigs (White et al. 2000, Brooks et al. 2001, Thompson & Weiner 2001, Morschauser et al. 2014, Rosenfeld & Roy 2014).
Vasculature changes during healthy human and rodent pregnancy and in post-partum period, relative to pre-pregnancy and/or non-pregnant control.
| Observation/species | Control | Early pregnancy | Mid-pregnancy | Late pregnancy | Post-partum | References |
|---|---|---|---|---|---|---|
| MAP | ||||||
| Human | 71–90 mmHg | 69–90 mmHg (↓) | 65–90 mmHg (↓) | 67–94 mmHg (−) | 72–93 mmHg (↓) | Kametas et al. (2001), Simmons et al. (2002), Bernstein et al. (2005), Gunderson et al. (2008), Morris et al. (2014, 2015), Melchiorre et al. (2016) |
| Rodent | Barron et al. (2010), Mirabito et al. (2014), Mirabito Colafella et al. (2017) | |||||
| Rats | 101–105 mmHg | 93–97 mmHg (↓) | N/A | N/A | N/A | |
| Mice | 90–103 mmHg | N/A | −4 to −8 mmHg (change in MAP, ↓) | +8 to +12 mmHg (change in MAP, −) | N/A | |
| UAD | ||||||
| Human | 1.3–1.5 mm | N/A | 2.6–3.0 mm (↑) | 3.0–3.6 mm (↑) | N/A | Palmer et al. (1992), Dickey & Hower (1995), Bernstein et al. (2002), Rigano et al. (2010), Ogueh et al. (2011) |
| Rodent | Cooke & Davidge (2003), van der Heijden et al. (2009), Barron et al. (2010), Morris et al. (2020) | |||||
| Rats | 150 µm | N/A | N/A | 190 µm (↑) | 150–190 µm (↑) | |
| Mice | N/A | N/A | N/A | ~150% non-pregnant control value (↑) | ~150% non-pregnant control value (↑) | |
| MADa | ||||||
| Rodent | Meyer et al. (1997), Cooke & Davidge (2003), Marshall et al. (2016), Morris et al. (2020) | |||||
| Rats | Lowest passive distensibility | N/A | N/A | Increased passive distensibility (↑) | Increased passive distensibility (↑) | |
| Mice | N/A | N/A | N/A | Increased methacholine-induced vasodilation, decreased L-NAME-induced constriction (↑) | N/A | |
| RVR | ||||||
| Human | Sims and Krantz (1958), Dunlop (1981), Sturgiss et al. (1996), Chapman et al. (1998), Dib et al. (2003), Ogueh et al. (2011) | |||||
| RI | 0.61–0.65 | 0.65–0.67 (↑) | 0.65–0.67 (↑) | 0.65–0.67 (↑) | 0.62 (−) | |
| RBF, mL/min | ~400–600 | ~700–1000 (↑) | ~600–1000 (↑) | ~400–700 (↑) | ||
| RVR, sec.cm−5 | ~7000 | ~3500–4500 (↓) | ~3500–4500 (↓) | ~3500–4500 (↓) | N/A | |
| Rodent (rats) | Matthews & Taylor (1960), Davison & Lindheimer (1980), Gandley et al. (2001), Novak et al. (2001) | |||||
| RBF, mL/L | 5.86–6.82 mL/min | 6.45–7.11 (−) | 8.48 (↑) | 5.44–7.44 (↑) | N/A | |
| RMR | 1.1–5.5 | N/A | 1.3–3.7 (↓) | N/A | N/A | |
| SAD | −3% increase | N/A | +8% (↓ vascular resistance) | N/A | N/A |
Renal blood flow (RBF) was measured using the para-aminohippurate clearance method. RVR was calculated using MAP and RBF. An increase in RBF and/or SAD reflects a decrease in renal vascular resistance. Renal resistance index (RI) was calculated using systolic and diastolic velocities.↓, decreased; ↑, increased; −: returned to non-pregnant/pre-pregnancy value. aNot investigated in humans. L-NAME, Nω-nitro-L-arginine methyl ester; MAD, mesenteric artery dilation; MAP, mean arterial pressure; N/A, no information available/yet investigated; RI, resistance index; RMR, renal myogenic reactivity; RVR, renal vascular resistance; SAD, small renal artery diameter; UAD, uterine artery dilation.
Roles of endothelial cells and endothelium-derived vasodilators
From the above, it is clear that there is a pregnancy-induced vasodilation effect on the maternal blood vessels, which can potentially be maintained post-partum. These physiological changes are mainly caused by activities of vascular endothelial cells and smooth muscle cells. Endothelial cells produce a number of vasodilators and vasoconstrictors, such as nitric oxide (NO) and endothelin 1, respectively, which transduce signals to the contractile vascular smooth muscle cells to control the constriction and dilation of blood vessels (Rensen et al. 2007, Sandoo et al. 2010, Gao et al. 2016, Touyz et al. 2018).
During pregnancy, there is an increase in the production of vasodilators by endothelial cells, as well as the sensitivity of endothelial cells themselves towards vasodilators. For instance, there is an increase in production of the vasodilators, NO and hydrogen sulphide, and the vasodilator-producing enzymes, endothelial NO synthase (eNOS) and cystathionine beta-synthase (CBS) in uterine artery endothelial cell (hUAEC) cultures from pregnant women at late gestation (week 35–36), compared to non-pregnant women (Zhang et al. 2017). Moreover, treatment of hUAECs with 10 ng/mL vascular endothelial growth factor, a vasodilator, resulted in an even higher protein expression of eNOS and CBS (Zhang et al. 2017). As expected, when the endothelium-derived vasodilators, such as NO synthase (NOS) (Cooke & Davidge 2003, Barron et al. 2010) or prostaglandin H synthase (Cooke & Davidge 2003) was inhibited (by Nomega-Nitro-l-arginine methyl ester hydrochloride (L-NAME) or meclofenamate, respectively) in pregnant rodents, the pregnancy-specific vasodilation effect, including the increase in blood vessel diameter and sensitivity towards methacholine of uterine arteries, was diminished or abolished (Cooke & Davidge 2003, Barron et al. 2010).
Similarly, in eNOS-deficient mice, the increase in uterine artery diameter until day 10 post-partum was eliminated (van der Heijden et al. 2009). The pregnancy-induced change in renal artery myogenic reactivity during midterm was also attenuated by the inhibition of either NOS or endothelin type B receptor (Gandley et al. 2001), or the removal of circulating relaxin (Novak et al. 2001), a 6-kDa ovarian peptide hormone that induces NO production of endothelial cells and, hence, functions as a vasodilator during pregnancy (Conrad 2011). Likewise, relaxin-deficient mice lost the pregnancy-specific increased sensitivity towards methacholine and decreased sensitivity towards Ang II in their mesenteric arteries (Leo et al. 2014a, Marshall et al. 2016).
There is evidence that there might also be an adaptation of the maternal vasculature system towards the aberrant vascular relaxation during pregnancy. Specifically, in the presence of L-NAME, myogenic tone (i.e. the capability to sustain vasoconstriction (Johansson 1989)) of uterine arteries in late pregnant rats decreased from 39 ± 3.2% to 11 ± 5.0%, whereas myogenic tone of uterine arteries in the non-pregnant control group increased from 5 ± 2.6% to 31 ± 3.1% (Barron et al. 2010), suggesting a pregnancy-induced re-modelling of uterine arteries that resulted in a decrease in arterial stiffness (Patzak et al. 2018) that was pregnancy specific in rats. Additionally, there was a greater uterine artery diameter in eNOS-deficient mice at 2 days post-partum compared to non-pregnant mice, proposing an alternative source of NO and/or an alternative relaxation pathway (van der Heijden et al. 2009).
Biochemical pathways of maternal blood vessel vasodilation in pregnancy
As mentioned earlier, endothelial cells produce vasoactive factors that interact with the smooth muscle cells to control the vascular function during pregnancy. Interestingly, endothelial cells and smooth muscle cells are also targets of other vasoconstrictors and vasodilators. In order to gain a better understanding of the underlying mechanisms of vascular adaptation to pregnancy, numerous studies have focused on the renin–angiotensin system and the peptide hormone relaxin. This section will highlight different biochemical pathways that are influenced by the factors mentioned earlier, which can cause blood vessel vasoconstriction or vasodilation.
Renin–angiotensin system
The renin–angiotensin system is known to have a significant effect on regulating blood pressure, including during pregnancy. While renin, a protease, is produced from juxtaglomerular cells of the kidney; angiotensinogen, the angiotensin precusor, is a product of the liver (Timmermans et al. 1993). The generation of biologically active Ang II, a vasoconstrictor, requires the cleavage of angiotensinogen by renin, in order to generate angiotensin I, which is converted to Ang II by the angiotensin-converting enzyme (ACE) (Timmermans et al. 1993). There are numerous Ang II receptors that have been extensively studied over the last few decades, two of which are angiotensin type 1 (AT1) receptor and angiotensin type 2 (AT2) receptor (Bottari et al. 1993). The two receptors, despite having a similar affinity towards Ang II, are distinguished by their different affinities towards antagonists that bind to them and later inhibit their binding to Ang II (Bottari et al. 1993). Additionally, AT1 and AT2 receptors are expressed in both vascular endothelial cells and vascular smooth muscle cells (Bottari et al. 1993, Allen et al. 2000, Henrion et al. 2001).
Early in pregnancy there is an increase in the maternal plasma Ang II level to stimulate the sodium absorbing and holding capability of blood vessels (Lumbers & Pringle 2014). This is suggested to be an adaptive mechanism that helps maintain homeostasis as the maternal cardiac output and blood volume increase during pregnancy (Irani & Xia 2011, Lumbers & Pringle 2014). Nonetheless, since the 1970s, researchers have reported a trend of weakened responsiveness of blood vessels in the midgestational period, represented by vascular resistance, towards the vasoconstriction effect of infused Ang II in normotensive, but not hypertensive, pregnant women (Gant et al. 1973). One of the potential explanations for the earlier observation is the pregnancy-specific enhanced AT2 receptor and/or decreased AT1 receptor expression (Takeda-Matsubara et al. 2004, Chen et al. 2007, Ferreira et al. 2009, Mirabito et al. 2014, Cunningham et al. 2016, 2018). In general, AT1 and AT2 receptors have opposite effects in regulating blood pressure, in both the non-pregnant state and during pregnancy (Irani & Xia 2008, Kawai et al. 2017). The binding of Ang II, dependent on the ratio of AT1/AT2 receptors, causes either a vasoconstriction or a vasodilation outcome, when the receptor is either AT1 or AT2, respectively (Chen et al. 2007). Lack of AT1 receptor expression in female transgenic Ang II-enhanced/AT1-knockout mice caused a significant decline in the systemic blood pressure (by 13% the WT mice) measured at mid-gestation (Chen et al. 2007). Meanwhile, inhibition of the AT2 receptor by an added antagonist (PD123319) in WT mice caused an increase in blood pressure (Chen et al. 2007). In AT2 receptor-knockout mice, mid-gestational MAP did not change from the pre-pregnancy value, whereas a significant reduction by 6 ± 2 mmHg was seen in WT mice (Mirabito et al. 2014). At gestational day 20, MAP of WT mice was similar to the pre-pregnancy value, while MAP of AT2 receptor-knockout mice increased by 13 ± 7 mmHg (Mirabito et al. 2014). Additionally, there was no change in the renal AT1 receptor mRNA expression in AT2 receptor-knockout mice, compared to a reduced expression in WT mice (Mirabito et al. 2014).
In rats, AT2 receptor mRNA expression measured in the maternal aorta, renal artery, and mesangial cells (main component of renal glomeruli in the renal cortex) at day 12–14 of pregnancy significantly increased compared to the non-pregnant control, whereas there were no changes in AT1 receptor mRNA expression (Ferreira et al. 2009). The Ang II-induced increase in calcium concentration in mesangial cells of pregnant rats was more than two-fold lower compared to the non-pregnant control, suggesting a reduction in sensitivity of renal cells towards Ang II in the midgestational period (Ferreira et al. 2009). On the contrary, Ang II-induced renal vascular resistance and renal mitochondrial oxidative stress at late gestation increased when the AT1 receptor function was enhanced by its agonist autoantibodies (AT1-AA), which are detectable in preeclamptic pregnancies (Cunningham et al. 2016, 2019). These phenotypes were reduced and/or inhibited by the AT1-AA inhibitor (‘n7AAc’) (Cunningham et al. 2018, 2019), suggesting the vasoconstriction-inducing effect of the AT1 receptor, which is usually decreased in a normal pregnancy but increased with preeclampsia. Further emphasising the importance of this system in pregnancy health and disease, in preeclampsia hypersensitivity of the AT1 receptor through its heterodimerisation leads to increased Ang II responsiveness (Abdalla et al. 2001b, Quitterer & Abdalla 2021).
In regards to different biochemical pathways that are activated by the binding of Ang II to a receptor, different consequential signalling cascades can lead to either vasoconstriction or vasodilation. For instance, when bound by Ang II, AT1 receptor interacts with heterotrimeric G-proteins, which then transduces signals to protein tyrosine kinase (PTK) and Rho guanine nucleotide exchange factors (Rho GEFs) (Kawai et al. 2017). Although PTK and Rho GEFs activate other molecules in different pathways, such as phosphoinositide-3-kinase (PIK3), phospholipase C, or Ras homolog family member A (RhoA) (Ushio-Fukai et al. 1998, Seki et al. 1999, Lutz et al. 2005), the final endpoint, vasoconstriction, is similar (Fig. 1). On the contrary, the binding of Ang II to the AT2 receptor inhibits the RhoA/Rho kinase pathway and causes vasodilation (Savoia et al. 2005) (Fig. 2). There are likely more molecules involved in these pathways that are yet to be discovered. Therefore, further research is required to determine which specific pathway(s) are altered as an adaptation to pregnancy.
Different pathways activated as a result of the binding of Angiotensin II to the AT1 receptor which result in vasoconstriction. Organs and/or cell types in which the pathways were studied are shown. →, activates/binds; −, inhibits. PRKC, protein kinase C; PTK, protein tyrosine kinase; PIK3, phosphoinositide-3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PKB, protein kinase B; PLC, phospholipase C; Rho GEFs, Rho guanine nucleotide exchange factors; IP3, inositol triphosphate; DAG, diacylglycerol; ROS, reactive oxygen species; CACC, calcium-activated chloride channel; MLCK, myosin light chain kinase; MLCP, myosin light chain phosphatase; ERK, extracellular-signal-regulated kinase; MAPK, mitogen-activated protein kinase; EDN1, endothelin 1; WNK3, with-no-lysine kinase 3; SPAK, STE20/SPS1-related proline/alanine-rich kinase; NKCC1, Na–K–Cl cotransporter isoform 1 (Aksoy et al. 1982, Yanagisawa et al. 1988, Sadoshima & Izumo 1993, Archer et al. 1994, Griendling et al. 1994, Eguchi et al. 1996, Ushio-Fukai et al. 1998, Seki et al. 1999, Takahashi et al. 1999, Touyz et al. 1999, 2001, 2004, Kubo et al. 2001, Quignard et al. 2001, Lutz et al. 2005, Qi et al. 2009, Abou-Saleh et al. 2013, Zeniya et al. 2013, Lin et al. 2014, Wang et al. 2015). Created with BioRender.com.
Citation: Reproduction 164, 4; 10.1530/REP-21-0428
Different pathways activated as a result of the binding of Angiotensin II to the AT2 receptor which result in vasodilation. Organs and/or cell types in which the pathways were studied are shown. →, activates/binds; −, inhibits. BK, bradykinin; NO, nitric oxide; cGMP, cyclic GMP; PRKC, protein kinase C; IP3, inositol triphosphate (Ignarro et al. 1986, Twort & Breemen 1988, Siragy & Carey 1996, Li et al. 1998, Schlossmann et al. 2000, Abdalla et al. 2001a , Savoia et al. 2005, Inuzuka et al. 2016). Created with BioRender.com.
Citation: Reproduction 164, 4; 10.1530/REP-21-0428
Relaxin
The Human 2 relaxin and its two orthologs in rodents, Mouse 1 relaxin and Rat 1 relaxin, are produced by the ovarian corpus luteum and the placenta (Sherwood 2004, Marshall et al. 2017c). The most studied role of relaxin is that on the mesenteric, renal, and uterine blood vessels. However, it likely also plays a role in the placental vasculature. Despite limited information regarding its functional role in the placenta, it has been shown to be important for the survival of cytotrophoblast cells (Conrad 2016, Marshall et al. 2017b).
Relaxin binds several receptors, including the relaxin/insulin‐like family peptide receptor 1 (RXFP1) (Jelinic et al. 2014), which is mostly found on the surface of vascular endothelial and vascular smooth muscle cells (Jelinic et al. 2014), except the human umbilical artery endothelial cells (Sarwar et al. 2016). Relaxin is known to play an essential role in blood vessel vasodilation, including during pregnancy, and the evidence of this role comes from both animal (Ferreira et al. 2009, McGuane et al. 2011, Vodstrcil et al. 2012, Leo et al. 2014b, Marshall et al. 2016, 2017a, Mirabito Colafella et al. 2017) and human (Quattrone et al. 2004, McGuane et al. 2011, Sarwar et al. 2016) studies. Relaxin-knockout mice have an elevated heart rate throughout pregnancy, in association with higher MAP compared to WT mice at both mid-gestation (gestational day 9; 9.7 mmHg higher) and late gestation (gestational day 19; 7.2 mmHg higher) (Mirabito Colafella et al. 2017). Moreover, the pregnancy-induced decreased sensitivity of mesenteric arteries towards the vasoconstriction effect of Ang II was eliminated in relaxin-deficient pregnant mice (Marshall et al. 2016). In contrast, when relaxin-deficient mice were treated with exogenous relaxin at days 12.5–17.5 of gestation, the Ang II-induced contraction of mesenteric arteries was reduced by more than half the contraction seen in untreated mice (Marshall et al. 2017a).
As both Ang II and relaxin are involved in the regulation of the maternal vasculature system during pregnancy, there is a question of whether relaxin interacts with any of the molecules/pathways induced by the binding of Ang II to its receptors. Indeed, the addition of exogenous relaxin (1000 ng/mL) into human umbilical vein endothelial cells (HUVECs) increased NOS II expression by 15 times compared to the untreated cells (Quattrone et al. 2004). Consequently, the protein expression of NOS II and the NO production were increased by more than double the untreated control. In support of this finding, the direct addition of serelaxin, a recombinant form of relaxin, into either human umbilical artery smooth muscle cell (HUASMC) or human umbilical vein smooth muscle cell (HUVSMC) monoculture induced cGMP accumulation within the smooth muscle cells (Sarwar et al. 2016), which interferes with the release of Ca2+ from the sarcoplasmic reticulum into the smooth muscle cell intracellular space, hence affecting its contractile phenotype (Touyz et al. 2018). This is known as one of the key steps involved in the Ang II-AT2-NO/cGMP pathway that can lead to vasodilation (Fig. 2). The addition of serelaxin into either HUVECs or human coronary artery endothelial cells that were co-cultured with HUASMCs and HUVSMCs also induced cGMP accumulation within the smooth muscle cells (Sarwar et al. 2016). Additionally, when the endothelial cells were treated with L‐NG‐nitro arginine (NOARG), a NOS inhibitor, the relaxin-induced cGMP accumulation was significantly reduced. Besides NO and cGMP, relaxin was also shown to cause a vasodilation effect via the activation of bradykinin (Leo et al. 2014b) and the PI3K-Akt pathway (Dimmeler et al. 1999, McGuane et al. 2011, Lian et al. 2018), which are also involved in the Ang II–AT1/AT2 receptor regulation of blood vessels (Figs 1 and 2). Taken together, relaxin interacts with various factors and pathways in endothelial and vascular smooth muscle cells leading to vasodilation.
These results, therefore, give rise to another question of whether relaxin interacts with the Ang II receptors. A study on rat renal myofibroblasts reported that relaxin treatment decreased renal fibrosis by increasing extracellular-signal-regulated kinase phosphorylation and NOS phosphorylation, by approximately double the untreated control, and decreasing expression of TGFB1, pSmad2, and alpha-smooth muscle actin to a similar level compared to the untreated control (Chow et al. 2014). However, these effects were abolished when the AT2 receptor activity was blocked by PD123319 or when there was no cell surface AT2 receptor expression (Chow et al. 2014). Bioluminescence resonance energy transfer saturation assays of human embryonic renal cells also confirmed the presence of RXFP1-AT2 receptor heterodimer when RXFP1 was bound by relaxin (Chow et al. 2014). Likewise, evidence of the RXFP-AT1 heterodimer was found in rat renal myofibroblasts (Chow et al. 2019) and human cardiac myofibroblasts (Chow et al. 2019, Wang et al. 2020), suggesting that Ang II receptors are important for the function of relaxin and that relaxin can indirectly activate the AT1/AT2 receptors function via the formation of RXFP1–AT1/AT2 complex. However, it is not clear whether there is a relaxin–Ang II receptor interaction in vascular endothelial and smooth muscle cells, and whether such event is responsible for the vasodilation of maternal blood vessels during pregnancy.
Besides relaxin and the renin–angiotensin system, there is a range of other factors, such as oestrogen and progesterone—the two sex hormones that also play important roles in remodelling of the maternal vascular system during pregnancy (Kodogo et al. 2019). Moreover, these hormones also interact with the renin–angiotensin system and pathways that are activated by the binding of Ang II to its receptors. Indeed increased levels of progesterone and prostacyclin may lead to resistance of Ang II effects (Gant et al. 1980, Irani & Xia 2011). An in-depth discussion on the role of these factors has been reviewed elsewhere (Lumbers & Pringle 2014, Wetendorf & Demayo 2014, Kodogo et al. 2019).
Ang II/relaxin in preeclampsia
The role of Ang II/relaxin in the maternal vasculature system during pregnancy is important for the investigation of aberrant haemodynamic functions in pregnancy complications such as preeclampsia (Lumbers et al. 2019). Briefly, in preeclampsia, abnormal placental development leads to the increased release of factors into the maternal circulation (including renin and AT1-AAs) and over-activation of the AT1 receptor and vasoconstriction. Moreover, low levels of relaxin in the first trimester have been identified in women who later develop late-onset preeclampsia (Post Uiterweer et al. 2020). A better understanding of the relationship between Ang II pathways and relaxin in uncomplicated pregnancies is critical to understand the role of relaxin in complications such as preeclampsia.
Future perspectives
Interestingly, endothelial and smooth muscle cells are mechanosensitive to changes in blood flow and blood pressure during pregnancy altering the shear stress and stretch these cells experience, which can in turn alter their expression and function (Boo et al. 2002, Rodríguez & González 2014, Jufri et al. 2015). Moreover, it is known that at least some of the relevant receptors within the relaxin–RXFP1–Ang II pathways are themselves mechanosensitive. For example, the AT1 receptor can be mechanically activated through an Ang II-independent mechanism and can lead to actin remodelling and changes in myogenic responsiveness (Hong et al. 2016). Therefore, dynamic cellular culture under shear stress may hold further insights and should be considered when studying interactions within these pathways, in vitro. For example, the use of organ-on-chip microfluidic models which better mimic specific aspects of the in vivo cellular physiological environment (Huh et al. 2011, Ganesan et al. 2017). Indeed, microfluidic models have been shown to recreate the mechanical forces and shear stress similar to what the cells would experience within blood vessels (Ostrowski et al. 2014, Gray & Stroka 2017, van Engeland et al. 2018). In addition, studies of animal models, in which functional responses of blood vessels can be measured using wire myography, pressure myography (Leo et al. 2014a, Marshall et al. 2016, 2017a, 2018) and arteriography (Morris et al. 2020), can be used to investigate vasodilation in regards to altered relaxin–Ang II receptor interaction at different time points during pregnancy and post-partum. This might allow future studies to look at similar changes in humans and provide prevention strategies or pathways for treatment.
Conclusion
In summary, it is important to understand the underlying mechanisms of maternal vasculature adaptation, such as relaxin–RXFP1–Ang II receptor interactions, in a healthy human pregnancy. This might help explain why there is potentially a protective effect on the vasculature system post-partum in women that have a healthy pregnancy. In addition, understanding the biochemical pathways involved in maternal vasculature adaptation to pregnancy may help shed light on how these pathways may be disrupted in pregnancy complicated by gestational hypertension or preeclampsia.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
M W would like to acknowledge the financial support of the National Health and Medical Research Council (Development grant: APP1171821).
Data availability statement
Data availability is not applicable to this article as no new data were created or analysed in this study.
Author contribution statement
T B M, L P, M W conception and design of article; T N A D literature search, data interpretation and manuscript drafting; T B M, L P, M W critical revision and contribution to intellectual content.
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