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

Abstract

BACKGROUND: Preeclampsia is a risk factor for the development of later-life cardiovascular disease. However, the underlying mechanisms are poorly understood. Excessive hypercholesteremia in pregnancy induces a preeclampsia-like phenotype, but whether this also impacts maternal vascular function later in life has not been fully characterized. METHODS AND RESULTS: Sprague Dawley rats received a control diet (CD) or a high-cholesterol (HCD) diet from gestational day 6 to 20, after which maternal vascular function was assessed 3 months postpartum. Exposure to an HCD in pregnancy reduced later-life endothelium-dependent vasodilation in carotid arteries (−15.24±3.27%), which was mediated via prostaglandin H synthase 2. There were no differences in vasodilation between CD and HCD postpartum rats in the mesenteric arteries, coronary arteries, or aortas. Vasoconstriction to phenylephrine increased in carotid arteries (61.02±21.48%) and reduced in aortas (−23.24±6.19%) of the HCD postpartum group versus CD dams, without differences in mesenteric and coronary ar-teries. The increased vasoconstriction in carotid arteries was due to lower nitric oxide modulation of constriction. Moreover, carotid artery myogenic response was reduced (−37.68±10.07%) and stiffness was increased (19.67±6.21%) in the HCD postpartum rats compared with CD along with decreased elastin density (−20.85±4.52%). The impact of the HCD on vascular function did not occur in age-matched never-pregnant female rats. CONCLUSIONS: Excessive hypercholesterolemia in pregnancy impairs later-life maternal vascular function in rats with varying impacts across different vascular beds. Understanding mechanisms for pregnancy-specific excessive hypercholesterolemia provides avenues for targeted intervention strategies to reduce the burden of cardiovascular disease in women who had a complicated pregnancy.