Alterations in endothelin type B receptor contribute to microvascular dysfunction in women who have had preeclampsia

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_BR). We evaluated ET-1 sensitivity, ET_AR, and ET_BR contributions to ET-1-mediated constriction, and the mechanistic role of ET_BR 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_BR-mediated dilation. We further hypothesized that ET_BR-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_AR-blockade), and ET-1 + 300 nmol/l BQ-788 (ET_BR-blockade), and during graded infusion of acetylcholine (ACh, 10⁻⁷–10² mmol/l) and a standardized local heating protocol with and without ET_BR-inhibition. PrEC had an increased vasoconstriction response to ET-1 (P=0.02). PrEC demonstrated reduced dilation responses to selective ET_BR stimulation with ET-1 (P=0.01). ET_BR-inhibition augmented ET-1-mediated constriction in HC (P=0.01) but attenuated ET-1-mediated constriction in PrEC (P=0.003). ET_BR-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_BR signaling. Furthermore, altered ET_BR function contributes to diminished endothelium-dependent dilation in previously preeclamptic women.