{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T08:09:35Z","timestamp":1787731775073,"version":"build-2784847793"},"reference-count":104,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,28]],"date-time":"2021-07-28T00:00:00Z","timestamp":1627430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["FS154313"],"award-info":[{"award-number":["FS154313"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010090","name":"Women and Children\u2019s Health Research Institute","doi-asserted-by":"publisher","award":["WCHRIIG2507"],"award-info":[{"award-number":["WCHRIIG2507"]}],"id":[{"id":"10.13039\/100010090","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010090","name":"Women and Children\u2019s Health Research Institute","doi-asserted-by":"publisher","award":["WCHRI Graduate Studentship"],"award-info":[{"award-number":["WCHRI Graduate Studentship"]}],"id":[{"id":"10.13039\/100010090","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019691","name":"Faculty of Medicine and Dentistry, University of Alberta","doi-asserted-by":"publisher","award":["75th Anniversary Award"],"award-info":[{"award-number":["75th Anniversary Award"]}],"id":[{"id":"10.13039\/501100019691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001804","name":"Canada Research Chairs","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001804","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Advanced maternal age (\u226535 years old) increases the risk of pregnancy complications such as preeclampsia and fetal growth restriction. We previously demonstrated vascular dysfunction and abnormal pregnancy outcomes in a rat model of advanced maternal age. However, vascular adaptations to pregnancy in aging were not studied. We hypothesize that advanced maternal age is associated with a more vasoconstrictive phenotype due to reduced nitric oxide (NO) and increased activity of matrix metalloproteinases (MMPs), contributing to impaired vascular adaptations to pregnancy. A rat model of advanced maternal age was used: young (4 months) and aged (9.5 months; \u223c35 years in humans) non-pregnant and pregnant rats. On gestational day 20 (term = 22 days; non-pregnant rats were aged-matched), blood pressure and heart rate were measured (tail cuff plethysmography) and vascular function was assessed in mesenteric arteries (wire myography). Endothelium-dependent relaxation to methylcholine (MCh) was assessed in the presence\/absence of nitric oxide synthase inhibitor (L-NAME), or inhibitors of endothelium-dependent hyperpolarization (EDH; apamin and TRAM-34). Vasoconstriction responses to big endothelin-1 (bigET-1), in the presence\/absence of MMPs-inhibitor (GM6001) or endothelin converting enzyme (ECE-1) inhibitor (CGS35066), in addition, ET-1 responsiveness, were measured. Blood pressure was elevated only in aged non-pregnant rats (<jats:italic>p<\/jats:italic>&amp;lt; 0.001) compared to all other groups. MCh responses were not different, however, L-NAME decreased maximum vasodilation in young (<jats:italic>p<\/jats:italic>&amp;lt; 0.01) and aged pregnant rats (<jats:italic>p<\/jats:italic>&amp;lt; 0.001), and decreased MCh sensitivity in young non-pregnant rats (<jats:italic>p<\/jats:italic>&amp;lt; 0.01), without effects in aged non-pregnant rats. EDH contribution to relaxation was similar in young non-pregnant, and aged non-pregnant and pregnant rats, while EDH-mediated relaxation was absent in young pregnant rats (<jats:italic>p<\/jats:italic>&amp;lt; 0.001). BigET-1 responses were enhanced in aged non-pregnant (<jats:italic>p<\/jats:italic>&amp;lt; 0.01) and pregnant rats (<jats:italic>p<\/jats:italic>&amp;lt; 0.05). No significant changes in bigET-1 conversion occurred in the presence of MMP-inhibitor, whereas ECE-1 inhibition reduced bigET-1 constriction in aged rats (<jats:italic>p<\/jats:italic>&amp;lt; 0.01). No differences in ET-1 sensitivity were observed. In conclusion, contrary to our hypothesis, reduced blood pressure, and an increased EDH-dependent contribution to vasodilation suggest a compensatory mechanism that may reflect beneficial adaptations in these aged rats that were able to maintain pregnancy. These data increase our understanding of how the vascular adaptive pathways in pregnancy compensate for advanced maternal age.<\/jats:p>","DOI":"10.3389\/fphys.2021.718568","type":"journal-article","created":{"date-parts":[[2021,7,28]],"date-time":"2021-07-28T16:02:36Z","timestamp":1627488156000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Altered Vascular Adaptations to Pregnancy in a Rat Model of Advanced Maternal Age"],"prefix":"10.3389","volume":"12","author":[{"given":"Mazhar","family":"Pasha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy L.","family":"Wooldridge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raven","family":"Kirschenman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Floor","family":"Spaans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra T.","family":"Davidge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christy-Lynn M.","family":"Cooke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1161\/hypertensionaha.111.00055","article-title":"Matrix metalloproteinase enhances big-endothelin-1 constriction in mesenteric vessels of pregnant rats with reduced uterine blood flow.","volume":"61","author":"Abdalvand","year":"2013","journal-title":"Hypertension"},{"key":"B2","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1081\/prg-120024025","article-title":"Endothelin converting enzyme (ECE) activity in normal pregnancy and preeclampsia.","volume":"22","author":"Ajne","year":"2003","journal-title":"Hypertens. Pregnancy"},{"key":"B3","doi-asserted-by":"crossref","first-page":"H1712","DOI":"10.1152\/ajpheart.00613.2020","article-title":"Maternal systemic vascular dysfunction in a primate model of defective uterine spiral artery remodeling.","volume":"320","author":"Albrecht","year":"2021","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1177\/1933719109345288","article-title":"Resistance artery adaptation to pregnancy counteracts the vasoconstricting influence of plasma from normal pregnant women.","volume":"17","author":"Amburgey","year":"2010","journal-title":"Reprod. Sci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.theriogenology.2007.09.021","article-title":"The pregnant sheep as a model for human pregnancy.","volume":"69","author":"Barry","year":"2008","journal-title":"Theriogenology"},{"key":"B6","doi-asserted-by":"crossref","first-page":"S89","DOI":"10.1097\/00004872-199715022-00009","article-title":"Large artery stiffness in hypertension.","volume":"15","author":"Benetos","year":"1997","journal-title":"J. Hypertens. Suppl."},{"key":"B7","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1111\/j.1447-0756.2008.00860.x","article-title":"Plasma nitric oxide, endothelin-1, arginase and superoxide dismutase in pre-eclamptic women.","volume":"34","author":"Bernardi","year":"2008","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"B8","doi-asserted-by":"crossref","first-page":"R27","DOI":"10.1530\/JOE-16-0340","article-title":"Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia.","volume":"232","author":"Boeldt","year":"2017","journal-title":"J. Endocrinol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1530\/joe-11-0053","article-title":"eNOS activation and NO function: pregnancy adaptive programming of capacitative entry responses alters nitric oxide (NO) output in vascular endothelium\u2013new insights into eNOS regulation through adaptive cell signaling.","volume":"210","author":"Boeldt","year":"2011","journal-title":"J. Endocrinol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.cardiores.2007.06.004","article-title":"The importance of endothelin-1 for vascular dysfunction in cardiovascular disease.","volume":"76","author":"Bohm","year":"2007","journal-title":"Cardiovasc. Res."},{"key":"B11","first-page":"434","article-title":"Age-related physiological changes and their clinical significance.","volume":"135","author":"Boss","year":"1981","journal-title":"West. J. Med."},{"key":"B12","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.cardiores.2004.12.027","article-title":"Endothelial aging.","volume":"66","author":"Brandes","year":"2005","journal-title":"Cardiovasc. Res."},{"key":"B13","author":"Canada","year":"2012","journal-title":"Births 2009"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.1161\/01.hyp.35.6.1237","article-title":"Interactions between nitric oxide and endothelin in the regulation of vascular tone of human resistance vessels in vivo.","volume":"35","author":"Cardillo","year":"2000","journal-title":"Hypertension"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1324","DOI":"10.1161\/hypertensionaha.115.05167","article-title":"Effect of advanced maternal age on pregnancy outcomes and vascular function in the rat.","volume":"65","author":"Care","year":"2015","journal-title":"Hypertension"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1165","DOI":"10.1111\/j.1476-5381.1988.tb11752.x","article-title":"Acetylcholine releases endothelium-derived hyperpolarizing factor and EDRF from rat blood vessels.","volume":"95","author":"Chen","year":"1988","journal-title":"Br. J. Pharmacol."},{"key":"B17","doi-asserted-by":"crossref","DOI":"10.1155\/2013\/928315","article-title":"Matrix metalloproteinases: inflammatory regulators of cell behaviors in vascular formation and remodeling.","volume":"2013","author":"Chen","year":"2013","journal-title":"Mediators Inflamm."},{"key":"B18","first-page":"257","article-title":"Nitric oxide production increases during normal pregnancy and decreases in preeclampsia.","volume":"32","author":"Choi","year":"2002","journal-title":"Ann. Clin. Lab. Sci."},{"key":"B19","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1159\/000158978","article-title":"Mesenteric arcade arteries contribute substantially to vascular resistance in conscious rats.","volume":"30","author":"Christensen","year":"1993","journal-title":"J. Vasc. Res."},{"key":"B20","first-page":"406","article-title":"Expression of metalloproteinases 1, 2, 7, 9, and 12 in human cytotrophoblastic cells from normal and preeclamptic placentas.","volume":"33","author":"Cohen","year":"2012","journal-title":"Neuro Endocrinol. Lett."},{"key":"B21","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1096\/fasebj.7.6.7682524","article-title":"Identification of increased nitric oxide biosynthesis during pregnancy in rats.","volume":"7","author":"Conrad","year":"1993","journal-title":"FASEB J."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1072","DOI":"10.1095\/biolreprod.102.009886","article-title":"Pregnancy-induced alterations of vascular function in mouse mesenteric and uterine arteries.","volume":"68","author":"Cooke","year":"2003","journal-title":"Biol. Reprod."},{"key":"B23","doi-asserted-by":"publisher","first-page":"5807","DOI":"10.1113\/jp275472","article-title":"Increased susceptibility to cardiovascular disease in offspring born from dams of advanced maternal age.","volume":"596","author":"Cooke","year":"2018","journal-title":"J. Physiol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"944","DOI":"10.1097\/00005344-199812000-00011","article-title":"Endothelium-dependent hyperpolarization in isolated arteries taken from animals treated with NO-synthase inhibitors.","volume":"32","author":"Corriu","year":"1998","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1067\/mva.2000.108010","article-title":"Increased matrix metalloproteinase 2 expression in vascular smooth muscle cells cultured from abdominal aortic aneurysms.","volume":"32","author":"Crowther","year":"2000","journal-title":"J. Vasc. Surg."},{"key":"B26","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1161\/01.res.73.1.79","article-title":"Cyclooxygenase-dependent vasoconstrictor alters vascular function in the vitamin E-deprived rat.","volume":"73","author":"Davidge","year":"1993","journal-title":"Circ. Res."},{"key":"B27","doi-asserted-by":"crossref","first-page":"353S","DOI":"10.1042\/CS103S353S","article-title":"Role of endothelin-converting enzyme, chymase and neutral endopeptidase in the processing of big ET-1, ET-1(1-21) and ET-1(1-31) in the trachea of allergic mice.","volume":"103","author":"De Campo","year":"2002","journal-title":"Clin. Sci. (Lond.)"},{"key":"B28","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1016\/j.lfs.2012.04.040","article-title":"Complex expression changes of the placental endothelin system in early and late onset preeclampsia, fetal growth restriction and gestational diabetes.","volume":"91","author":"Dieber-Rotheneder","year":"2012","journal-title":"Life Sci."},{"key":"B29","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1161\/01.hyp.34.3.375","article-title":"Isolated systolic hypertension : prognostic information provided by pulse pressure.","volume":"34","author":"Domanski","year":"1999","journal-title":"Hypertension"},{"key":"B30","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1161\/circresaha.118.312563","article-title":"Mechanisms of dysfunction in the aging vasculature and role in age-related disease.","volume":"123","author":"Donato","year":"2018","journal-title":"Circ. Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"5127","DOI":"10.12659\/msm.916287","article-title":"Age-related impairment of structure and function of iliac artery endothelium in rats is improved by elevated fluid shear stress.","volume":"25","author":"Dong","year":"2019","journal-title":"Med. Sci. Monit."},{"key":"B32","first-page":"H821","article-title":"Normal pregnancy is associated with enhanced endothelium-dependent flow-mediated vasodilation.","volume":"276","author":"Dorup","year":"1999","journal-title":"Am. J. Physiol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1016\/j.phrs.2011.01.012","article-title":"Endothelin-1 and diabetic complications: focus on the vasculature.","volume":"63","author":"Ergul","year":"2011","journal-title":"Pharmacol. Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1161\/01.hyp.0000170460.24604.23","article-title":"Endothelin-1 (1-31) is an intermediate in the production of endothelin-1 after big endothelin-1 administration in vivo.","volume":"46","author":"Fecteau","year":"2005","journal-title":"Hypertension"},{"key":"B35","doi-asserted-by":"publisher","first-page":"2591","DOI":"10.1152\/japplphysiol.00601.2003","article-title":"Invited review: aging and the cardiovascular system.","volume":"95","author":"Ferrari","year":"2003","journal-title":"J. Appl. Physiol. (1985)"},{"key":"B36","doi-asserted-by":"publisher","first-page":"2323","DOI":"10.1161\/01.cir.97.23.2323","article-title":"Inhibition of neutral endopeptidase causes vasoconstriction of human resistance vessels in vivo.","volume":"97","author":"Ferro","year":"1998","journal-title":"Circulation"},{"key":"B37","first-page":"S29","article-title":"Ageing and hypertension: the assessment of blood pressure indices in predicting coronary heart disease.","volume":"17","author":"Franklin","year":"1999","journal-title":"J. Hypertens. Suppl."},{"key":"B38","doi-asserted-by":"publisher","first-page":"2015","DOI":"10.1016\/j.bbamcr.2017.05.007","article-title":"The role of matrix metalloproteinases in aging: tissue remodeling and beyond.","author":"Freitas-Rodriguez","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"B39","first-page":"H509","article-title":"Age-related changes in endothelium-dependent hyperpolarization in the rat mesenteric artery.","author":"Fujii","year":"1993","journal-title":"Am. J. Physiol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1038\/ajh.2011.95","article-title":"Maternal age during pregnancy is associated with third trimester blood pressure level: the generation R study.","volume":"24","author":"Gaillard","year":"2011","journal-title":"Am. J. Hypertens."},{"key":"B41","first-page":"63","article-title":"The children of older first-time mothers in Canada: their health and development.","volume":"64","author":"Garner","year":"2008","journal-title":"Genus"},{"key":"B42","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1038\/sj.bjp.0702099","article-title":"Enhanced acetylcholine induced relaxation in small mesenteric arteries from pregnant rats: an important role for endothelium-derived hyperpolarizing factor (EDHF).","volume":"125","author":"Gerber","year":"1998","journal-title":"Br. J. Pharmacol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1161\/circresaha.109.210229","article-title":"Increased endothelial exocytosis and generation of endothelin-1 contributes to constriction of aged arteries.","volume":"107","author":"Goel","year":"2010","journal-title":"Circ. Res."},{"key":"B44","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1111\/j.1440-1681.2004.04054.x","article-title":"Changes in endothelium-derived hyperpolarizing factor in hypertension and ageing: response to chronic treatment with renin-angiotensin system inhibitors.","volume":"31","author":"Goto","year":"2004","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.yjmcc.2015.04.011","article-title":"Vascular biology of ageing-Implications in hypertension.","volume":"83","author":"Harvey","year":"2015","journal-title":"J. Mol. Cell. Cardiol."},{"key":"B46","doi-asserted-by":"crossref","first-page":"H684","DOI":"10.1152\/ajpheart.00538.2006","article-title":"Induction of matrix metalloproteinase-2 enhances systemic arterial contraction after hypoxia.","volume":"292","author":"He","year":"2007","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"B47","first-page":"211","article-title":"Nitric oxide biosynthesis during normal pregnancy and pregnancy complicated by preeclampsia.","volume":"14","author":"Hodzic","year":"2017","journal-title":"Med. Glas. (Zenica)"},{"key":"B48","doi-asserted-by":"publisher","first-page":"2139","DOI":"10.1113\/jphysiol.2011.206623","article-title":"Age-related changes in skeletal muscle reactive oxygen species generation and adaptive responses to reactive oxygen species.","author":"Jackson","year":"2011","journal-title":"J. Physiol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.exger.2017.05.016","article-title":"Physical activity and cardiovascular aging: physiological and molecular insights.","volume":"109","author":"Jakovljevic","year":"2018","journal-title":"Exp. Gerontol."},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1186\/s12884-018-1984-x","article-title":"The effect of advanced maternal age on perinatal outcomes in nulliparous singleton pregnancies.","volume":"18","author":"Kahveci","year":"2018","journal-title":"BMC Pregnancy Childbirth"},{"key":"B51","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1042\/cs1030067","article-title":"Differential mechanisms of endothelium-dependent vasodilator responses in human myometrial small arteries in normal pregnancy and pre-eclampsia.","volume":"103","author":"Kenny","year":"2002","journal-title":"Clin. Sci. (Lond.)"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0056583","article-title":"Advanced maternal age and adverse pregnancy outcome: evidence from a large contemporary cohort.","volume":"8","author":"Kenny","year":"2013","journal-title":"PLoS One."},{"key":"B53","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1002\/uog.12494","article-title":"Maternal age and adverse pregnancy outcome: a cohort study.","volume":"42","author":"Khalil","year":"2013","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20184411","article-title":"Vascular endothelial cell biology: an update.","volume":"20","author":"Kruger-Genge","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B55","doi-asserted-by":"publisher","first-page":"2212","DOI":"10.1016\/j.febslet.2012.06.020","article-title":"Endothelin converting Enzyme-1 phosphorylation and trafficking.","volume":"586","author":"Kuruppu","year":"2012","journal-title":"FEBS Lett."},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2393-12-47","article-title":"Preeclampsia complicated by advanced maternal age: a registry-based study on primiparous women in Finland 1997-2008.","volume":"12","author":"Lamminpaa","year":"2012","journal-title":"BMC Pregnancy Childbirth"},{"key":"B57","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-017-09814-w","article-title":"Placental dysfunction underlies increased risk of fetal growth restriction and stillbirth in advanced maternal age women.","volume":"7","author":"Lean","year":"2017","journal-title":"Sci. Rep."},{"key":"B58","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.1253\/circj.CJ-10-0910","article-title":"Aging and arterial stiffness.","volume":"74","author":"Lee","year":"2010","journal-title":"Circ J."},{"key":"B59","doi-asserted-by":"crossref","first-page":"R509","DOI":"10.1152\/ajpregu.00656.2009","article-title":"Endothelin in the female vasculature: a role in aging?","volume":"298","author":"Lekontseva","year":"2010","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"B60","doi-asserted-by":"crossref","first-page":"757","DOI":"10.2147\/CIA.S158513","article-title":"Oxidative stress, aging, and diseases.","volume":"13","author":"Liguori","year":"2018","journal-title":"Clin. Interv. Aging"},{"key":"B61","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1016\/j.cardiores.2004.11.029","article-title":"Age-dependent changes in myocardial matrix metalloproteinase\/tissue inhibitor of metalloproteinase profiles and fibroblast function.","volume":"66","author":"Lindsey","year":"2005","journal-title":"Cardiovasc. Res."},{"key":"B62","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1111\/j.1479-828x.2012.01442.x","article-title":"Pregnancy outcomes for nulliparous women of advanced maternal age in South Australia, 1998-2008.","volume":"52","author":"Ludford","year":"2012","journal-title":"Aust. N. Z. J. Obstet. Gynaecol."},{"key":"B63","doi-asserted-by":"crossref","first-page":"R1102","DOI":"10.1152\/ajpregu.00550.2003","article-title":"The mechanism of EDHF-mediated responses in subcutaneous small arteries from healthy pregnant women.","volume":"286","author":"Luksha","year":"2004","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"B64","doi-asserted-by":"crossref","first-page":"C481","DOI":"10.1152\/ajpcell.00147.2020","article-title":"Extracellular matrix dynamics in vascular remodeling.","volume":"319","author":"Ma","year":"2020","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"B65","first-page":"H1914","article-title":"Endothelial vasodilator production by uterine and systemic arteries. I. Effects of ANG II on PGI2 and NO in pregnancy.","author":"Magness","year":"1996","journal-title":"Am. J. Physiol."},{"key":"B66","first-page":"H1730","article-title":"Endothelial vasodilator production by uterine and systemic arteries. II. Pregnancy effects on NO synthase expression.","author":"Magness","year":"1997","journal-title":"Am. J. Physiol."},{"key":"B67","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1159\/000329821","article-title":"Endothelial-derived hyperpolarization factor (EDHF) contributes to PlGF-induced dilation of mesenteric resistance arteries from pregnant rats.","volume":"49","author":"Mandala","year":"2012","journal-title":"J. Vasc. Res."},{"key":"B68","first-page":"1","article-title":"Births: final data for 2006.","volume":"57","author":"Martin","year":"2009","journal-title":"Natl. Vital Stat. Rep."},{"key":"B69","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1002\/cphy.c140043","article-title":"Cardiac physiology of pregnancy.","volume":"5","author":"May","year":"2015","journal-title":"Compr Physiol."},{"key":"B70","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1111\/j.1471-0528.1995.tb11428.x","article-title":"Nitric oxide synthase activities in placental tissue from normotensive, pre-eclamptic and growth retarded pregnancies.","volume":"102","author":"Morris","year":"1995","journal-title":"Br. J. Obstet. Gynaecol."},{"key":"B71","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-019-53199-x","article-title":"Advanced maternal age compromises fetal growth and induces sex-specific changes in placental phenotype in rats.","volume":"9","author":"Napso","year":"2019","journal-title":"Sci. Rep."},{"key":"B72","year":"1995","journal-title":"Nutrient Requirements of Laboratory Animals: Fourth Revised Edition, 1995."},{"key":"B73","doi-asserted-by":"publisher","first-page":"1419","DOI":"10.1111\/j.1745-7254.2008.00905.x","article-title":"Endothelium-derived hyperpolarizing factor mediated relaxations in pig coronary arteries do not involve Gi\/o proteins.","volume":"29","author":"Ng","year":"2008","journal-title":"Acta Pharmacol. Sin."},{"key":"B74","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1016\/s0002-9378(97)70611-2","article-title":"Gestation increases nitric oxide-mediated vasodilation in rat uterine arteries.","volume":"176","author":"Ni","year":"1997","journal-title":"Am. J. Obstet. Gynecol."},{"key":"B75","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1152\/physiol.00033.2008","article-title":"Maternal uterine vascular remodeling during pregnancy.","volume":"24","author":"Osol","year":"2009","journal-title":"Physiology (Bethesda)"},{"key":"B76","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1111\/micc.12080","article-title":"Maternal uterine vascular remodeling during pregnancy.","volume":"21","author":"Osol","year":"2014","journal-title":"Microcirculation"},{"key":"B77","doi-asserted-by":"crossref","DOI":"10.1186\/s40748-017-0072-y","article-title":"Serum nitric oxide levels in healthy pregnant women: a case- control study in a tertiary facility in Ghana.","volume":"4","author":"Owusu Darkwa","year":"2018","journal-title":"Matern Health Neonatol. Perinatol."},{"key":"B78","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1161\/01.hyp.30.4.837","article-title":"A live-cell assay for studying extracellular and intracellular endothelin-converting enzyme activity.","volume":"30","author":"Parnot","year":"1997","journal-title":"Hypertension"},{"key":"B79","first-page":"H1899","article-title":"Contraction and endothelium-dependent relaxation in mesenteric microvessels from pregnant rats.","author":"Pascoal","year":"1995","journal-title":"Am. J. Physiol."},{"key":"B80","doi-asserted-by":"publisher","first-page":"1649","DOI":"10.1007\/s11357-020-00219-8","article-title":"Advanced maternal age impacts physiologic adaptations to pregnancy in vervet monkeys.","volume":"42","author":"Plant","year":"2020","journal-title":"Geroscience"},{"key":"B81","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1016\/j.nut.2005.04.002","article-title":"Comparing rat\u2019s to human\u2019s age: how old is my rat in people years?","volume":"21","author":"Quinn","year":"2005","journal-title":"Nutrition"},{"key":"B82","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1111\/j.1447-0756.2008.00855.x","article-title":"Advanced maternal age and risk of antepartum and intrapartum stillbirth.","volume":"34","author":"Salihu","year":"2008","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"B83","doi-asserted-by":"crossref","first-page":"H1724","DOI":"10.1152\/ajpheart.00375.2018","article-title":"Sex-specific effects of advanced maternal age on cardiovascular function in aged adult rat offspring.","volume":"315","author":"Shah","year":"2018","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"B84","first-page":"861","article-title":"Endothelial modulation of vascular relaxation to nitrovasodilators in aging and hypertension.","volume":"239","author":"Shirasaki","year":"1986","journal-title":"J Pharmacol. Exp. Ther."},{"key":"B85","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1124\/jpet.108.142992","article-title":"Chymase-dependent conversion of big endothelin-1 in the mouse in vivo.","volume":"328","author":"Simard","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B86","first-page":"R441","article-title":"Nitric oxide and pregnancy.","author":"Sladek","year":"1997","journal-title":"Am. J. Physiol."},{"key":"B87","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1097\/hco.0b013e328302f3c6","article-title":"Endothelin-1, aging and hypertension.","volume":"23","author":"Stauffer","year":"2008","journal-title":"Curr. Opin. Cardiol."},{"key":"B88","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/j.hfc.2011.08.011","article-title":"Aging-associated cardiovascular changes and their relationship to heart failure.","volume":"8","author":"Strait","year":"2012","journal-title":"Heart Fail. Clin."},{"key":"B89","doi-asserted-by":"publisher","first-page":"2053","DOI":"10.1084\/jem.20080106","article-title":"Crucial role of nitric oxide synthases system in endothelium-dependent hyperpolarization in mice.","volume":"205","author":"Takaki","year":"2008","journal-title":"J. Exp. Med."},{"key":"B90","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1038\/sj.bjp.0706735","article-title":"Enzymatic pathways involved in the generation of endothelin-1(1-31) from exogenous big endothelin-1 in the rabbit aorta.","volume":"148","author":"Tirapelli","year":"2006","journal-title":"Br. J. Pharmacol."},{"key":"B91","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.pharmthera.2011.10.004","article-title":"Age-related changes in endothelial function and blood flow regulation.","volume":"133","author":"Toda","year":"2012","journal-title":"Pharmacol. Ther."},{"key":"B92","doi-asserted-by":"crossref","DOI":"10.1186\/1477-7827-7-79","article-title":"Vasodilator factors in the systemic and local adaptations to pregnancy.","volume":"7","author":"Valdes","year":"2009","journal-title":"Reprod. Biol. Endocrinol."},{"key":"B93","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.phrs.2003.11.015","article-title":"Endothelium-dependent hyperpolarizations: the history.","volume":"49","author":"Vanhoutte","year":"2004","journal-title":"Pharmacol. Res."},{"key":"B94","doi-asserted-by":"crossref","first-page":"H2226","DOI":"10.1152\/ajpheart.00593.2002","article-title":"Vascular adaptations to pregnancy in mice: effects on myogenic tone.","volume":"283","author":"Veerareddy","year":"2002","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"B95","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1111\/j.1476-5381.2009.00240.x","article-title":"Endothelium-dependent contractions and endothelial dysfunction in human hypertension.","volume":"157","author":"Versari","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"B96","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/0002-9378(89)90463-8","article-title":"Clinical significance of elevated mean arterial blood pressure in second trimester and threshold increase in systolic or diastolic blood pressure during third trimester.","volume":"160","author":"Villar","year":"1989","journal-title":"Am. J. Obstet. Gynecol."},{"key":"B97","doi-asserted-by":"crossref","first-page":"325","DOI":"10.3233\/CH-131713","article-title":"Enhanced matrix metalloproteinases-2 activates aortic endothelial hypermeability, apoptosis and vascular rarefaction in spontaneously hypertensive rat.","volume":"57","author":"Wang","year":"2014","journal-title":"Clin. Hemorheol. Microcirc."},{"key":"B98","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1161\/HYPERTENSIONAHA.114.03618","article-title":"Matrix metalloproteinases promote arterial remodeling in aging, hypertension, and atherosclerosis.","volume":"65","author":"Wang","year":"2015","journal-title":"Hypertension"},{"key":"B99","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1161\/01.HYP.0000014506.13322.66","article-title":"Altered regulation of matrix metalloproteinase-2 in aortic remodeling during aging.","volume":"39","author":"Wang","year":"2002","journal-title":"Hypertension"},{"key":"B100","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1161\/HYPERTENSIONAHA.112.191270","article-title":"Chronic matrix metalloproteinase inhibition retards age-associated arterial proinflammation and increase in blood pressure.","volume":"60","author":"Wang","year":"2012","journal-title":"Hypertension"},{"key":"B101","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1042\/CS20100475","article-title":"Endothelin-1 vasoconstriction and the age-related decline in endothelium-dependent vasodilatation in men.","volume":"120","author":"Westby","year":"2011","journal-title":"Clin. Sci. (Lond.)"},{"key":"B102","first-page":"H748","article-title":"Nitric oxide-mediated vasodilation in human pregnancy.","author":"Williams","year":"1997","journal-title":"Am. J. Physiol."},{"key":"B103","doi-asserted-by":"crossref","first-page":"590","DOI":"10.14336\/AD.2017.0430","article-title":"Age-related impairment of vascular structure and functions.","volume":"8","author":"Xu","year":"2017","journal-title":"Aging Dis."},{"key":"B104","first-page":"628","article-title":"Advanced maternal age and the risk of down syndrome characterized by the meiotic stage of chromosomal error: a population-based study.","volume":"58","author":"Yoon","year":"1996","journal-title":"Am. J. Hum. Genet."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.718568\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,6]],"date-time":"2023-11-06T15:59:52Z","timestamp":1699286392000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.718568\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,28]]},"references-count":104,"alternative-id":["10.3389\/fphys.2021.718568"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2021.718568","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,28]]},"article-number":"718568"}}