Advanced Maternal Age Impairs Uterine Artery Remodelling in the Pregnant Rat

Abstract

Advanced maternal age (AMA, ≥35 years) pregnancies are increasingly common, and are at increased risk for pregnancy complications. We previously showed that ex vivo uterine artery constriction due to increasing intraluminal pressures (myogenic tone) was greater in arteries of AMA vs. young pregnant rats. Aging impairs vascular reactivity and increases vascular stiffness via structural changes (e.g. increased collagen), however, the impact of AMA on adaptations to pregnancy in the uterine artery is unknown. We hypothesized that functional and structural uterine artery adaptations to pregnancy are impaired in aged compared with young rats.Pregnant young (4 months) and aged (9 months; ~35 years in humans) rats were studied on gestational day 20 (term=22 days) with age‐matched non‐pregnant rats. Uterine arteries were isolated and mounted in a pressure myograph. Active tone (calcium present in buffer, n=6‐10) and mechanical properties (circumferential stress and strain; calcium absent, n=10‐24) were assessed. Myogenic tone, circumferential stress and strain were calculated from active and passive curves. Collagen and elastin in the tunica media and intima (combined) were visualized with Masson’s trichrome (collagen) or Verhoeff’s (elastin) stains (n=4‐6). Data are mean area under the curve (AUC, myography) or % positive area (histology) ± SEM; analyzed by two‐way ANOVA with Sidak post‐hoc tests (significance: p<0.05).Between 4‐100 mmHg, myogenic tone did not change with age or pregnancy. However, arteries from young pregnant rats displayed forced vasodilation at higher pressures (100‐160 mmHg) that did not occur in arteries from other groups (p<0.0001). Circumferential stress and strain (Figure 1) increased with pregnancy (p<0.0001) but was significantly lower in arteries from pregnant AMA compared to young pregnant dams (p<0.05). Collagen and elastin (% positive areas) did not change with age or pregnancy overall, however, arteries from young non‐pregnant rats had greater collagen:elastin ratios than those from aged non‐pregnant rats (p=0.021). Arteries from aged non‐pregnant, young pregnant and AMA rats had similar ratios.This study illustrates that aging impacts both structural and functional adaptations of uterine arteries during pregnancy. The lower compliancy of arteries from AMA rats may be due to increased crosslinking of the existing collagen within the artery, as it was not explained by collagen:elastin ratio. These structural differences may contribute to the functional differences, potentially reducing uteroplacental blood supply. Thus, impaired uterine artery adaptations may increase the risk of pregnancy complications in women of advanced age.