Maternal exposure to an enriched environment promotes uterine vascular remodeling and prevents embryo loss in mice

in Reproduction
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  • 1 Laboratorio de Fisiología y Farmacología de la Reproducción, Centro de Estudios Farmacológicos y Botánicos, UBA-CONICET, Ciudad Autónoma de Buenos Aires CP, Argentina
  • | 2 Laboratorio de Fisiopatología de la Preñez y el Parto, Centro de Estudios Farmacológicos y Botánicos, UBA-CONICET, Ciudad Autónoma de Buenos Aires CP, Argentina

Correspondence should be addressed to J S Beltrame; Email: jbeltrame@fmed.uba.ar
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Implantation-related events are crucial for pregnancy success. In particular, defects in vascular remodeling at the maternal–fetal interface are associated with spontaneous miscarriage and recurrent pregnancy loss. Physical activity and therapies oriented to reduce stress improve pregnancy outcomes. In animal models, environmental stimulation and enrichment are associated with enhanced well-being, cognitive function and stress resilience. Here, we studied whether the exposure of BALB/c mice to an enriched environment (EE) regulates crucial events during early gestation at the maternal–fetal interface. Pregnant BALB/c mice were exposed to the EE that combines non-invasive stimuli from the sensory pathway with voluntary physical activity. The pregnancy rate was evaluated. Implantation sites were investigated microscopically and macroscopically. Vascular adaptation parameters at the maternal–fetal interface were analyzed. We found that exposure to the EE prevented pregnancy loss between gestational days 7 and 15. Also, it increased the diameter of the uterine artery and decreased the wall:lumen ratio of the mesometrial decidual vessels, suggesting that EE exposure promotes vascular remodeling. Moreover, it increased nitric oxide synthase activity and inducible nitric oxide synthase expression, as well as prostaglandin F2a production and endoglin expression in the implantation sites. Exposure of pregnant females to the EE regulates uterine physiology, promoting vascular remodeling during early gestation. These adaptations might contribute to preventing embryo loss. Our results highlight the importance of the maternal environment for pregnancy success. The design of an ‘EE-like’ protocol for humans could be considered as a new non-pharmacologic strategy to prevent implantation failure and recurrent miscarriage.

 

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  • ACOG 2020 Physical activity and exercise during pregnancy and the postpartum period. Obstetrics and Gynecology 135 e178e188. (https://doi.org/10.1097/AOG.0000000000003772)

    • Search Google Scholar
    • Export Citation
  • Ali M, Buhimschi I, Chwalisz K & Garfield RE 1997 Changes in expression of the nitric oxide synthase isoforms in rat uterus and cervix during pregnancy and parturition. Molecular Human Reproduction 3 9951003. (https://doi.org/10.1093/molehr/3.11.995)

    • Search Google Scholar
    • Export Citation
  • Bakos J, Hlavacova N, Rajman M, Ondicova K, Koros C, Kitraki E, Steinbusch HWM & Jezova D 2009 Enriched environment influences hormonal status and hippocampal brain derived neurotrophic factor in a sex dependent manner. Neuroscience 164 788797. (https://doi.org/10.1016/j.neuroscience.2009.08.054)

    • Search Google Scholar
    • Export Citation
  • Balthazar J, Schöwe NM, Cipolli GC, Buck HS & Viel TA 2018 Enriched environment significantly reduced senile plaques in a transgenic mice model of Alzheimer’s disease, improving memory. Frontiers in Aging Neuroscience 10 288. (https://doi.org/10.3389/fnagi.2018.00288)

    • Search Google Scholar
    • Export Citation
  • Baryla M, Kaczynski P, Goryszewska E, Riley SC & Waclawik A 2019 Prostaglandin F2α stimulates adhesion, migration, invasion and proliferation of the human trophoblast cell line HTR-8/SVneo. Placenta 77 1929. (https://doi.org/10.1016/j.placenta.2019.01.020)

    • Search Google Scholar
    • Export Citation
  • Beltrame JS, Sordelli MS, Cella M, Perez Martinez S, Franchi AM & Ribeiro ML 2013 Lysophosphatidic acid increases the production of pivotal mediators of decidualization and vascularization in the rat uterus. Placenta 34 751756. (https://doi.org/10.1016/j.placenta.2013.06.001)

    • Search Google Scholar
    • Export Citation
  • Beltrame JS, Sordelli MS, Cañumil VA, Franchi AM & Ribeiro ML 2018 Lysophosphatidic acid-triggered pathways promote the acquisition of trophoblast endovascular phenotype in vitro. Journal of Cellular Biochemistry 119 758772. (https://doi.org/10.1002/jcb.26239)

    • Search Google Scholar
    • Export Citation
  • Boivin J, Bunting L, Collins JA & Nygren KG 2007 International estimates of infertility prevalence and treatment-seeking: potential need and demand for infertility medical care. Human Reproduction 22 15061512. (https://doi.org/10.1093/humrep/dem046)

    • Search Google Scholar
    • Export Citation
  • Brosens I, Brosens JJ, Muter J, Puttemans P & Benagiano G 2019a Preeclampsia: the role of persistent endothelial cells in uteroplacental arteries. American Journal of Obstetrics and Gynecology 221 219226. (https://doi.org/10.1016/j.ajog.2019.01.239)

    • Search Google Scholar
    • Export Citation
  • Brosens I, Puttemans P & Benagiano G 2019b Placental bed research: I. The placental bed: from spiral arteries remodeling to the great obstetrical syndromes. American Journal of Obstetrics and Gynecology 221 437456. (https://doi.org/10.1016/j.ajog.2019.05.044)

    • Search Google Scholar
    • Export Citation
  • Burkuš J, Kačmarová M, Kubandová J, Kokošová N, Fabianová K, Fabian D, Koppel J & Čikoš Š 2015 Stress exposure during the preimplantation period affects blastocyst lineages and offspring development. Journal of Reproduction and Development 61 325331. (https://doi.org/10.1262/jrd.2015-012)

    • Search Google Scholar
    • Export Citation
  • Callegari EA, Ferguson-Gottschall S & Gibori G 2005 PGF2alpha induced differential expression of genes involved in turnover of extracellular matrix in rat decidual cells. Reproductive Biology and Endocrinology 3 3. (https://doi.org/10.1186/1477-7827-3-3)

    • Search Google Scholar
    • Export Citation
  • Cao L, Liu X, Lin EJ, Wang C, Choi EY, Riban V, Lin B & During MJ 2010 Environmental and genetic activation of a brain-adipocyte BDNF/leptin axis causes cancer remission and inhibition. Cell 142 5264. (https://doi.org/10.1016/j.cell.2010.05.029)

    • Search Google Scholar
    • Export Citation
  • Caporali P, Cutuli D, Gelfo F, Laricchiuta D, Foti F, De Bartolo P, Angelucci F & Petrosini L 2015 Interaction does count: a cross-fostering study on transgenerational effects of pre-reproductive maternal enrichment. Frontiers in Behavioral Neuroscience 9 320. (https://doi.org/10.3389/fnbeh.2015.00320)

    • Search Google Scholar
    • Export Citation
  • Cartwright JE, Fraser R, Leslie K, Wallace AE & James JL 2010 Remodelling at the maternal–fetal interface: relevance to human pregnancy disorders. Reproduction 140 803813. (https://doi.org/10.1530/REP-10-0294)

    • Search Google Scholar
    • Export Citation
  • Chadchan SB, Kumar V, Maurya VK, Soni UK & Jha RK 2016 Endoglin (CD105) coordinates the process of endometrial receptivity for embryo implantation. Molecular and Cellular Endocrinology 425 6983. (https://doi.org/10.1016/j.mce.2016.01.014)

    • Search Google Scholar
    • Export Citation
  • Douglas NC, Tang H, Gomez R, Pytowski B, Hicklin DJ, Sauer CM, Kitajewski J, Sauer MV & Zimmermann RC 2009 Vascular endothelial growth factor Receptor 2 (VEGFR-2) functions to promote uterine decidual angiogenesis during early pregnancy in the mouse. Endocrinology 150 38453854. (https://doi.org/10.1210/en.2008-1207)

    • Search Google Scholar
    • Export Citation
  • Dunkel Schetter C & Tanner L 2012 Anxiety, depression and stress in pregnancy: implications for mothers, children, research, and practice. Current Opinion in Psychiatry 25 141148. (https://doi.org/10.1097/YCO.0b013e3283503680)

    • Search Google Scholar
    • Export Citation
  • ESHRE Guideline Group on RPL, Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, Middeldorp S, Nelen W, Peramo B & Quenby S et al.2018 ESHRE guideline: recurrent pregnancy loss. Human Reproduction Open 2018 hoy004. (https://doi.org/10.1093/hropen/hoy004)

    • Search Google Scholar
    • Export Citation
  • Goldstein EZ, Pertsovskaya V, Forbes TA, Dupree JL & Gallo V 2021 Prolonged environmental enrichment promotes developmental myelination. Frontiers in Cell and Developmental Biology 9 665409. (https://doi.org/10.3389/fcell.2021.665409)

    • Search Google Scholar
    • Export Citation
  • Hamilton GS & Kennedy TG 1994 Uterine vascular changes after unilateral intrauterine infusion of indomethacin and prostaglandin E2 to rats sensitized for the decidual cell reaction. Biology of Reproduction 50 757764. (https://doi.org/10.1095/biolreprod50.4.757)

    • Search Google Scholar
    • Export Citation
  • Hinman SK, Smith KB, Quillen DM & Smith MS 2015 Exercise in pregnancy: a clinical review. Sports Health 7 527531. (https://doi.org/10.1177/1941738115599358)

    • Search Google Scholar
    • Export Citation
  • Jungling A, Reglodi D, Karadi ZN, Horvath G, Farkas J, Gaszner B & Tamas A 2017 Effects of postnatal enriched environment in a model of Parkinson’s disease in adult rats. International Journal of Molecular Sciences 18 406. (https://doi.org/10.3390/ijms18020406)

    • Search Google Scholar
    • Export Citation
  • Kaczynski P, Kowalewski MP & Waclawik A 2016 Prostaglandin F2α promotes angiogenesis and embryo–maternal interactions during implantation. Reproduction 151 539552. (https://doi.org/10.1530/REP-15-0496)

    • Search Google Scholar
    • Export Citation
  • Kaczynski P, Goryszewska E, Baryla M & Waclawik A 2020 Prostaglandin F2α stimulates angiogenesis at the embryo-maternal interface during early pregnancy in the pig. Theriogenology 142 169176. (https://doi.org/10.1016/j.theriogenology.2019.09.046)

    • Search Google Scholar
    • Export Citation
  • Kapur NK, Morine KJ & Letarte M 2013 Endoglin: a critical mediator of cardiovascular health. Vascular Health and Risk Management 9 195206. (https://doi.org/10.2147/VHRM.S29144)

    • Search Google Scholar
    • Export Citation
  • Kawamura K, Kawamura N, Sato W, Fukuda J, Kumagai J & Tanaka T 2009 Brain-derived neurotrophic factor promotes implantation and subsequent placental development by stimulating trophoblast cell growth and survival. Endocrinology 150 37743782. (https://doi.org/10.1210/en.2009-0213)

    • Search Google Scholar
    • Export Citation
  • Khankin EV, Mandala M, Colton I, Karumanchi SA & Osol G 2012 Hemodynamic, vascular, and reproductive impact of FMS-like tyrosine kinase 1 (FLT1) blockade on the uteroplacental circulation during normal mouse Pregnancy1. Biology of Reproduction 86 57. (https://doi.org/10.1095/biolreprod.111.095380)

    • Search Google Scholar
    • Export Citation
  • Kim M, Park HJ, Seol JW, Jang JY, Cho YS, Kim KR, Choi Y, Lydon JP, DeMayo FJ & Shibuya M et al.2013 VEGF‐A regulated by progesterone governs uterine angiogenesis and vascular remodelling during pregnancy. EMBO Molecular Medicine 5 14151430. (https://doi.org/10.1002/emmm.201302618)

    • Search Google Scholar
    • Export Citation
  • Krause BJ, Hanson MA & Casanello P 2011 Role of nitric oxide in placental vascular development and function. Placenta 32 797805. (https://doi.org/10.1016/j.placenta.2011.06.025)

    • Search Google Scholar
    • Export Citation
  • Langdon KD & Corbett D 2012 Improved working memory following novel combinations of physical and cognitive activity. Neurorehabilitation and Neural Repair 26 523532. (https://doi.org/10.1177/1545968311425919)

    • Search Google Scholar
    • Export Citation
  • Lebrin F, Goumans MJ, Jonker L, Carvalho RLC, Valdimarsdottir G, Thorikay M, Mummery C, Arthur HM & Dijke ten P 2004 Endoglin promotes endothelial cell proliferation and TGF-β/ALK1 signal transduction. EMBO Journal 23 40184028. (https://doi.org/10.1038/sj.emboj.7600386)

    • Search Google Scholar
    • Export Citation
  • Mannaerts D, Faes E, Cos P, Briedé JJ, Gyselaers W, Cornette J, Gorbanev Y, Bogaerts A, Spaanderman M & Van Craenenbroeck E et al.2018 Oxidative stress in healthy pregnancy and preeclampsia is linked to chronic inflammation, iron status and vascular function. PLoS ONE 13 e0202919. (https://doi.org/10.1371/journal.pone.0202919)

    • Search Google Scholar
    • Export Citation
  • Mano Y, Kotani T, Shibata K, Matsumura H, Tsuda H, Sumigama S, Yamamoto E, Iwase A, Senga T & Kikkawa F 2011 The loss of endoglin promotes the invasion of extravillous trophoblasts. Endocrinology 152 43864394. (https://doi.org/10.1210/en.2011-1088)

    • Search Google Scholar
    • Export Citation
  • Mansour AG, Xiao R, Bergin SM, Huang W, Chrislip LA, Zhang J, Ali S, Queen NJ, Caligiuri MA & Cao L 2021 Enriched environment enhances NK cell maturation through hypothalamic BDNF in male mice. European Journal of Immunology 51 557–566. (https://doi.org/10.1002/eji.201948358)

    • Search Google Scholar
    • Export Citation
  • Marie C, Pedard M, Quirié A, Tessier A, Garnier P, Totoson P & Demougeot C 2018 Brain-derived neurotrophic factor secreted by the cerebral endothelium: a new actor of brain function? Journal of Cerebral Blood Flow and Metabolism 38 935949. (https://doi.org/10.1177/0271678X18766772)

    • Search Google Scholar
    • Export Citation
  • Massey AJ, Campbell BK, Raine-Fenning N, Pincott-Allen C, Perry J & Vedhara K 2016 Relationship between hair and salivary cortisol and pregnancy in women undergoing IVF. Psychoneuroendocrinology 74 397405. (https://doi.org/10.1016/j.psyneuen.2016.08.027)

    • Search Google Scholar
    • Export Citation
  • Matvienko-Sikar K, Lee L, Murphy G & Murphy L 2016 The effects of mindfulness interventions on prenatal well-being: a systematic review. Psychology and Health 31 14151434. (https://doi.org/10.1080/08870446.2016.1220557)

    • Search Google Scholar
    • Export Citation
  • Mering S & Jolkkonen J 2015 Proper housing conditions in experimental stroke studies-special emphasis on environmental enrichment. Frontiers in Neuroscience 9 106. (https://doi.org/10.3389/fnins.2015.00106)

    • Search Google Scholar
    • Export Citation
  • Meuchel LW, Thompson MA, Cassivi SD, Pabelick CM & Prakash YS 2011 Neurotrophins induce nitric oxide generation in human pulmonary artery endothelial cells. Cardiovascular Research 91 668676. (https://doi.org/10.1093/cvr/cvr107)

    • Search Google Scholar
    • Export Citation
  • Novaro V, Colman-Lerner A, Ortega FV, Jawerbaum A, Paz D, Nostro Lo F, Pustovrh C, Gimeno MF & González E 2001 Regulation of metalloproteinases by nitric oxide in human trophoblast cells in culture. Reproduction, Fertility, and Development 13 411–420. (https://doi.org/10.1071/rd01036)

    • Search Google Scholar
    • Export Citation
  • Osol G & Mandala M 2009 Maternal uterine vascular remodeling during pregnancy. Physiology 24 5871. (https://doi.org/10.1152/physiol.00033.2008)

    • Search Google Scholar
    • Export Citation
  • Ota H, Igarashi S, Oyama N, Suzuki Y & Tanaka T 1999 Optimal levels of nitric oxide are crucial for implantation in mice. Reproduction, Fertility, and Development 11 183–188. (https://doi.org/10.1071/rd99044)

    • Search Google Scholar
    • Export Citation
  • Ozmen A, Unek G & Korgun ET 2017 Effect of glucocorticoids on mechanisms of placental angiogenesis. Placenta 52 4148. (https://doi.org/10.1016/j.placenta.2017.02.015)

    • Search Google Scholar
    • Export Citation
  • Patrizio P & Silber S 2017 Improving IVF: is there a limit to our ability to manipulate human biology? Journal of Assisted Reproduction and Genetics 34 79. (https://doi.org/10.1007/s10815-016-0828-8)

    • Search Google Scholar
    • Export Citation
  • Plaisier M, Dennert I, Rost E, Koolwijk P, van Hinsbergh VWM & Helmerhorst FM 2009 Decidual vascularization and the expression of angiogenic growth factors and proteases in first trimester spontaneous abortions. Human Reproduction 24 185197. (https://doi.org/10.1093/humrep/den296)

    • Search Google Scholar
    • Export Citation
  • Purcell TL, Given R, Chwalisz K & Garfield RE 1999 Nitric oxide synthase distribution during implantation in the mouse. Molecular Human Reproduction 5 467475. (https://doi.org/10.1093/molehr/5.5.467)

    • Search Google Scholar
    • Export Citation
  • Quenby S, Nik H, Innes B, Lash G, Turner M, Drury J & Bulmer J 2009 Uterine natural killer cells and angiogenesis in recurrent reproductive failure. Human Reproduction 24 4554. (https://doi.org/10.1093/humrep/den348)

    • Search Google Scholar
    • Export Citation
  • Sahay AS, Sundrani DP & Joshi SR 2017 Neurotrophins: role in placental growth and development. Vitamins and Hormones 104 243261. (https://doi.org/10.1016/bs.vh.2016.11.002)

    • Search Google Scholar
    • Export Citation
  • Sano K, Kawashima M, Imada T, Suzuki T, Nakamura S, Mimura M, Tanaka KF & Tsubota K 2019 Enriched environment alleviates stress-induced dry-eye through the BDNF axis. Scientific Reports 9 3422. (https://doi.org/10.1038/s41598-019-39467-w)

    • Search Google Scholar
    • Export Citation
  • Schander JA, Aisemberg J, Correa F, Wolfson ML, Juriol L, Cymeryng C, Jensen F & Franchi AM 2020 The enrichment of maternal environment prevents pre-term birth in a mice model. Reproduction 159 479492. (https://doi.org/10.1530/REP-19-0572)

    • Search Google Scholar
    • Export Citation
  • Schander JA, Marvaldi C, Correa F, Wolfson ML, Cella M, Aisemberg J, Jensen F & Franchi AM 2021 Maternal environmental enrichment modulates the immune response against an inflammatory challenge during gestation and protects the offspring. Journal of Reproductive Immunology 144 103273. (https://doi.org/10.1016/j.jri.2021.103273)

    • Search Google Scholar
    • Export Citation
  • Schlecht A, Vallon M, Wagner N, Ergün S & Braunger BM 2021 TGFβ-neurotrophin interactions in heart, retina, and brain. Biomolecules 11 1360. (https://doi.org/10.3390/biom11091360)

    • Search Google Scholar
    • Export Citation
  • Sominsky L, Hodgson DM, McLaughlin EA, Smith R, Wall HM & Spencer SJ 2017 Linking stress and infertility: a novel role for ghrelin. Endocrine Reviews 38 432467. (https://doi.org/10.1210/er.2016-1133)

    • Search Google Scholar
    • Export Citation
  • Sordelli MS, Beltrame JS, Burdet J, Zotta E, Pardo R, Cella M, Franchi AM & Ribeiro ML 2011 The effect of anandamide on uterine nitric oxide synthase activity depends on the presence of the blastocyst. PLoS ONE 6 e18368. (https://doi.org/10.1371/journal.pone.0018368)

    • Search Google Scholar
    • Export Citation
  • Sordelli MS, Beltrame JS, Cella M, Franchi AM & Ribeiro ML 2012 Cyclooxygenase-2 prostaglandins mediate anandamide-inhibitory action on nitric oxide synthase activity in the receptive rat uterus. European Journal of Pharmacology 685 174179. (https://doi.org/10.1016/j.ejphar.2012.04.034)

    • Search Google Scholar
    • Export Citation
  • Sordelli MS, Beltrame JS, Zotta E, Gomez N, Dmytrenko G, Sales ME, Blois SM, Davio C, Martinez SP & Franchi AM et al.2017 Endogenous lysophosphatidic acid participates in vascularisation and decidualisation at the maternal–fetal interface in the rat. Reproduction, Fertility and Development 29 2112. (https://doi.org/10.1071/RD16235)

    • Search Google Scholar
    • Export Citation
  • Stocco CO & Deis RP 1998 Participation of intraluteal progesterone and prostaglandin F2 alpha in LH-induced luteolysis in pregnant rat. Journal of Endocrinology 156 253259. (https://doi.org/10.1677/joe.0.1560253)

    • Search Google Scholar
    • Export Citation
  • WHO 2012. Global prevalence of infertility, infecundity and childlessness. In Sexual and reproductive health.

  • Windsperger K, Dekan S, Pils S, Golletz C, Kunihs V, Fiala C, Kristiansen G, Knöfler M & Pollheimer J 2017 Extravillous trophoblast invasion of venous as well as lymphatic vessels is altered in idiopathic, recurrent, spontaneous abortions. Human Reproduction 32 12081217. (https://doi.org/10.1093/humrep/dex058)

    • Search Google Scholar
    • Export Citation
  • Yuan C, Li X, Song H, Fan L, Su S & Dong B 2019 BMP7 coordinates endometrial epithelial cell receptivity for blastocyst implantation through the endoglin pathway in cell lines and a mouse model. Experimental and Therapeutic Medicine 17 25472556. (https://doi.org/10.3892/etm.2019.7265)

    • Search Google Scholar
    • Export Citation
  • Zhan Y, Li MZ, Yang L, Feng XF, Lei JF, Zhang N, Zhao YY & Zhao H 2020 The three-phase enriched environment paradigm promotes neurovascular restorative and prevents learning impairment after ischemic stroke in rats. Neurobiology of Disease 146 105091. (https://doi.org/10.1016/j.nbd.2020.105091)

    • Search Google Scholar
    • Export Citation
  • Zhang D, Liu H, Zeng J, Miao X, Huang W, Chen H, Huang Y, Li Y & Ye D 2016 Glucocorticoid exposure in early placentation induces preeclampsia in rats via interfering trophoblast development. General and Comparative Endocrinology 225 6170. (https://doi.org/10.1016/j.ygcen.2015.09.019)

    • Search Google Scholar
    • Export Citation
  • Zhang X, Chen XP, Lin JB, Xiong Y, Liao WJ & Wan Q 2017 Effect of enriched environment on angiogenesis and neurological functions in rats with focal cerebral ischemia. Brain Research 1655 176185. (https://doi.org/10.1016/j.brainres.2016.11.001)

    • Search Google Scholar
    • Export Citation