Excessive Hypercholesterolemia in Pregnancy Impairs Later-life Maternal Vascular Function in Rats

Abstract

Background: Preeclampsia is a significant risk factor for the development of later-life cardiovascular disease; however, the underlying molecular mechanisms are not fully understood. Studies have shown that excessive hypercholesteremia occurring during pregnancy increases the risk of vascular pregnancy complications, such as preeclampsia. Bioavailability of nitric oxide (NO), a critical endothelium-derived vasodilator in pregnancy, is reduced in both hypercholesteremia and preeclampsia. However, the later-life vascular impact of excessive pregnancy-specific hypercholesteremia is not known. Hypothesis: Excessive hypercholesteremia in pregnancy impairs later-life maternal vascular function by reducing NO availability. Methods: Sprague-Dawley rats were fed a control diet (CD) or high cholesterol diet (HCD; 2% cholesterol + 0.5% cholic acid) from gestational day 6 to 20 (term=22 days; n=10-12). After pregnancy, all dams received a CD. Three months after pregnancy (equal to ~10 years in humans), mesenteric (systemic resistance arteries) and carotid (vascular bed that supplies blood to the cerebral vasculature) arteries were isolated, and endothelium-dependent (to methacholine, MCh) and -independent (to sodium nitroprusside, SNP) vasodilation, plus vasoconstriction responses (to phenylephrine, PE) were assessed using wire myography. NO contribution was assessed using a pan-NO synthase inhibitor (L-NAME; 100 μmol). Data were summarized as maximum responses (Emax), sensitivity (pEC50), or delta Emax (control vs. L-NAME). The statistical tests applied were a Student’s t-test or two-way ANOVA with Sidak’s post-hoc test (significance: p<0.05). Results: In mesenteric arteries, vasodilation to MCh or SNP was not different between the CD and HCD groups three months after the insult. However, L-NAME reduced maximum vasodilation to MCh in the HCD group (p=0.0433) but not in CD animals. Similarly, vasoconstriction to PE was not different between groups, but L-NAME increased the PE sensitivity in the HCD group (p=0.0423), without effects in the CD animals. In carotid arteries, a HCD during pregnancy reduced vasodilation to MCh (p=0.0345), and while L-NAME prevented vasodilation to MCh in both groups (p<0.0001), this effect was more pronounced in the HCD compared to CD group (delta Emax, p=0.0422). Vasodilation to SNP was similar between groups. Vasoconstriction responses to PE were increased in carotid arteries of HCD compared to CD animals (p=0.0357). L-NAME increased PE-mediated vasoconstriction in both groups (CD: 4.32-fold and HCD: 2.71-fold), but this NO modulation was significantly less in the HCD group compared to CD (delta Emax, p=0.0337). Conclusion: Exposure to a HCD, during pregnancy only, impaired later-life maternal vascular function in carotid, but not mesenteric arteries, suggesting vascular-bed specific effects in animals with a history of preeclampsia. Moreover, a HCD during pregnancy altered the NO pathway in both vascular beds, indicating that long-term alterations in NO were established during pregnancy. In summary, excessive pregnancy-specific hypercholesterolemia contributes to later-life maternal vascular dysfunction via modulation of the NO pathway, which may help explain the increased cardiovascular risk after preeclampsia. This work was supported by a foundation grant from the Canadian Institutes of Health Research (CIHR FS154313) and by the Women and Children’s Health Research Institute (WCHRI) through the generosity of the Stollery Children’s Hospital Foundation and the Alberta Women’s Health Foundation. A.A.O. is supported by a WCHRI postdoctoral fellowship through the generosity of the Stollery Children’s Hospital Foundation and the Alberta Women’s Health Foundation. E.E. was supported by a summer research studentship from Alberta Innovates. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.