Altered Vascular Adaptations to Pregnancy in a Rat Model of Advanced Maternal Age

Abstract

Advanced maternal age (≥35 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; ∼35 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 (p < 0.001) compared to all other groups. MCh responses were not different, however, L-NAME decreased maximum vasodilation in young (p < 0.01) and aged pregnant rats (p < 0.001), and decreased MCh sensitivity in young non-pregnant rats (p < 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 (p < 0.001). BigET-1 responses were enhanced in aged non-pregnant (p < 0.01) and pregnant rats (p < 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 (p < 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.

The Effect of Tauroursodeoxycholic Acid (TUDCA) Treatment on Pregnancy Outcomes and Vascular Function in a Rat Model of Advanced Maternal Age

“…These findings contrast with other studies, which showed that TUDCA increased NO bioavailability by reducing ER stress and improved vascular function in mesenteric arteries and aorta from tunicamycin-treated mice and in db/db mice [44,56]. A potential explanation for these differences in vascular outcomes after TUDCA treatment could be that the other studies were conducted in non-pregnant rodents, and chemically induced ER stress causes pronounced vascular endothelial dysfunction with reduced NO, which is not what we observed with advanced maternal age rats [14]. Further, the rat age of our model may not be sufficiently old enough to affect endothelium-dependent relaxation in mesenteric arteries, as it is possible that age-related vascular changes are ongoing.…”

“…In a previous study, we observed altered vascular to pregnancy in mesenteric arteries of aged dams compared to young dams [ 14 ]. Given the association of ER stress with adverse pregnancy outcomes ([ 27 , 47 ], we speculated that ER stress may be involved in mediating this vascular dysfunction.…”

“…After finding signs of systemic vascular ER stress, together with (previously reported) impaired pregnancy outcomes and altered vascular function [ 14 ]; we wanted to assess if pregnancy outcomes and vascular function could be improved by ameliorating ER stress. To the best of our knowledge, we are the first to assess the effect of an ER stress inhibitor, such as TUDCA, on pregnancy outcomes and vascular function in a rat model of complicated pregnancy.…”

“…In a rat model of advanced maternal age, we have demonstrated adverse pregnancy outcomes and a reduced capacity to sustain a pregnancy, reduced fetal weight, altered vascular function in systemic arteries, and increased active myogenic responses in both mesenteric and uterine arteries from aged dams compared to young dams [ 11 , 12 ]. In addition, other animal models of advanced maternal age (mouse and vervet/African green monkey) have also shown impaired vascular adaptations during pregnancy with advanced maternal age, that were associated with poor pregnancy outcomes and altered vascular function [ 13 , 14 ]. Although pregnancies at advanced maternal age are considered high-risk clinically, the underlying pathophysiological molecular mechanisms associated with the adverse pregnancy outcomes, particularly related to vascular dysfunction in advanced maternal age are not well established.…”

Advanced Maternal Age Impairs Uterine Artery Adaptations to Pregnancy in Rats

“…We used a previously established rat model of advanced maternal age [ 38 , 63 , 64 , 65 ]. Aged rats at 9.5 months of age correspond to ~35 years of age in humans, based on milestones such as weaning, skeletal and sexual maturity, and reproductive senescence, and young control rats at 3.5–4 months of age correspond to ~early reproductive maturity in humans [ 63 , 66 ].…”