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Alterations in endothelin type B receptor contribute to microvascular dysfunction in women who have had preeclampsia
Journal article   Peer reviewed

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

Anna E Stanhewicz, Sandeep Jandu, Lakshmi Santhanam and Lacy M Alexander
Clinical science (1979), Vol.131(23), pp.2777-2789
12/22/2017
DOI: 10.1042/CS20171292
PMCID: PMC5922254
PMID: 29042489

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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 R). We evaluated ET-1 sensitivity, ET R, and ET R contributions to ET-1-mediated constriction, and the mechanistic role of ET R 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 ET R-mediated dilation. We further hypothesized that ET 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 -10 mol/l), ET-1 + 500 nmol/l BQ-123 (ET R-blockade), and ET-1 + 300 nmol/l BQ-788 (ET R-blockade), and during graded infusion of acetylcholine (ACh, 10 -10 mmol/l) and a standardized local heating protocol with and without ET R-inhibition. PrEC had an increased vasoconstriction response to ET-1 ( =0.02). PrEC demonstrated reduced dilation responses to selective ET R stimulation with ET-1 ( =0.01). ET R-inhibition augmented ET-1-mediated constriction in HC ( =0.01) but attenuated ET-1-mediated constriction in PrEC ( =0.003). ET R-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 ET R signaling. Furthermore, altered ET R function contributes to diminished endothelium-dependent dilation in previously preeclamptic women.
 Acetylcholine - pharmacology Adult Biopsy Endothelin-1 - pharmacology Endothelium, Vascular - drug effects Endothelium, Vascular - pathology Endothelium, Vascular - physiopathology Female Galvanic Skin Response Humans Microdialysis Microvessels - metabolism Microvessels - physiopathology Nitric Oxide - pharmacology Norepinephrine - pharmacology Pre-Eclampsia - metabolism Pre-Eclampsia - physiopathology Pregnancy Receptor, Endothelin A Receptor, Endothelin B - metabolism Signal Transduction - drug effects Skin - pathology Vasoconstriction - drug effects Vasodilation - drug effects Young Adult

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