Maternal aging impacts vascular adaptations to pregnancy

Introduction
Advanced maternal age (≥35 years) increases the risk of pregnancy complications, which may be due to poor cardiovascular adaptations to pregnancy in aged women. Aging is associated with vascular stiffness and endothelial dysfunction. Enhanced oxidative stress with reduced nitric oxide (NO) bioavailability and increased activity of vasoconstrictors, such as endothelin-1 (ET-1), may contribute to these aging-related vascular abnormalities. However, whether these vascular changes linked to aging affect vascular adaptations during pregnancy, and contribute to endothelial dysfunction, remains unknown. We hypothesize that vascular adaptations are impaired by maternal aging, due to altered NO-and ET-1-dependent mechanisms.
Methods
We used non-pregnant and pregnant young (4 months of age) and aged rats (9.5 months of age; equivalent to ~35 years of human age); n=6-10/group. Blood pressure was measured (CODA tail-cuff system) on gestational day 20 (term=22 days), or in aged matched non-pregnant rats, and rats were euthanized. Mesenteric arteries were isolated to assess vascular function ex vivo using wire myography. Endothelium-dependent relaxation to methacholine (MCh) was assessed and L-NAME (pan nitric oxide [NO] synthase inhibitor), or apocynin (inhibitor of NADPH oxidase; an enzyme that induces oxidative stress) were used to assess the contribution of those pathways. Vasoconstriction responses to big-endothelin-1 (bET-1) and ET-1 were evaluated to assess constrictor capacity; CGS (an inhibitor of endothelin converting enzyme: ECE) was used to measure ECE contribution. Data were analyzed by two-way ANOVA with Sidak’s post-test, p<0.05 was considered significant. Results Mean arterial blood pressure (MAP) was highest in aged non-pregnant rats (p=0.025). Interestingly, MAP in aged pregnant rats was similar to MAP in both the young groups. Mch-induced vasodilation responses were not different between groups. However, pretreatment with L-NAME (NO contribution to vasodilation) decreased maximum vasodilation in young (p=0.027) and aged pregnant rats (p=0.001) and decreased MCh sensitivity in young nonpregnant rats (p<0.0001), without effects in aged non-pregnant rats. Pretreatment with apocynin (to assess NADPH oxidase activity) increased MCh sensitivity in aged non-pregnant rats only (p=0.029). Vasoconstriction to bET-1 did not change during pregnancy but were higher in aged versus young pregnant rats (p=0.009); while ET-1 responses were similar between groups. The contribution of ECEs in converting bigET-1 to ET-1 (control vs. CGS curve) was higher in aged pregnant (p=0.012) and non-pregnant rats (p=0.015), compared to young controls. Conclusion A higher MAP in aged non-pregnant rats may be due to a constrictive systemic vasculature. The lower MAP and enhanced NO-mediated vasodilation in aged pregnant rats may reflect adaptations to maintain pregnancy. In contrast, pregnancy in aged rats did not alter other aging-related effects, like the higher bET-1 responses and ECE contribution, highlighting the complex cardiovascular adaptations required for a successful pregnancy in aged rats. Overall, advanced age is associated with altered cardiovascular function in non-pregnant rats, while these changes appear to be compensated during pregnancy