Abstract
Microvascular dysfunction originating during a preeclamptic pregnancy persists postpartum and probably contributes to increased CVD risk in these women. One putative mechanism contributing to this dysfunction is increased vasoconstrictor sensitivity to endothelin-1 (ET-1), mediated by alterations in ET-1 receptor type-B (ET(B)R). We evaluated ET-1 sensitivity, ET(A)R, and ET(B)R contributions to ET-1-mediated constriction, and the mechanistic role of ET(B)R in endothelium-dependent dilation in vivo in the microvasculature of postpartum women who had preeclampsia (PrEC, n=12) and control women who had a healthy pregnancy (HC, n=12). We hypothesized that (1) PrEC would have a greater vasoconstrictor response to ET-1, and (2) reduced ET(B)R-mediated dilation. We further hypothesized that ET(B)R-blockade would attenuate endothelium-dependent vasodilation in HC, but not PrEC. Microvascular reactivity was assessed by measurement of cutaneous vascular conductance responses to graded infusion of ET-1 (10(-20)-10(-8) mol/l), ET-1 + 500 nmol/l BQ-123 (ET(A)R-blockade), and ET-1 + 300 nmol/l BQ-788 (ET(B)R-blockade), and during graded infusion of acetylcholine (ACh, 10(-7)-10(2) mmol/l) and a standardized local heating protocol with and without ET(B)R-inhibition. PrEC had an increased vasoconstriction response to ET-1 (P=0.02). PrEC demonstrated reduced dilation responses to selective ET(B)R stimulation with ET-1 (P=0.01). ET(B)R-inhibition augmented ET-1-mediated constriction in HC (P=0.01) but attenuated ET-1-mediated constriction in PrEC (P=0.003). ET(B)R-inhibition attenuated endothelium-dependent vasodilation responses to 100mmol/l ACh (P=0.04) and local heat (P=0.003) in HC but increased vasodilation (ACh: P=0.01; local heat: P=0.03) in PrEC. Women who have had preeclampsia demonstrate augmented vasoconstrictor sensitivity to ET-1, mediated by altered ET(B)R signaling. Furthermore, altered ET(B)R function contributes to diminished endothelium-dependent dilation in previously preeclamptic women.