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 (ETR). We evaluated ET-1 sensitivity, ETR, and ETR contributions to ET-1-mediated constriction, and the mechanistic role of ETR in endothelium-dependent dilation in the microvasculature of postpartum women who had preeclampsia (PrEC, =12) and control women who had a healthy pregnancy (HC, =12). We hypothesized that (1) PrEC would have a greater vasoconstrictor response to ET-1, and (2) reduced ETR-mediated dilation. We further hypothesized that ETR-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 (10-10 mol/l), ET-1 + 500 nmol/l BQ-123 (ETR-blockade), and ET-1 + 300 nmol/l BQ-788 (ETR-blockade), and during graded infusion of acetylcholine (ACh, 10-10 mmol/l) and a standardized local heating protocol with and without ETR-inhibition. PrEC had an increased vasoconstriction response to ET-1 (=0.02). PrEC demonstrated reduced dilation responses to selective ETR stimulation with ET-1 (=0.01). ETR-inhibition augmented ET-1-mediated constriction in HC (=0.01) but attenuated ET-1-mediated constriction in PrEC (=0.003). ETR-inhibition attenuated endothelium-dependent vasodilation responses to 100mmol/l ACh (=0.04) and local heat (=0.003) in HC but increased vasodilation (ACh: =0.01; local heat: =0.03) in PrEC. Women who have had preeclampsia demonstrate augmented vasoconstrictor sensitivity to ET-1, mediated by altered ETR signaling. Furthermore, altered ETR function contributes to diminished endothelium-dependent dilation in previously preeclamptic women.