Role of Endothelin Type B Receptors in Microvascular Dysfunction Post‐partum in Women Who Have Had Preeclampsia

Abstract

Women with a history of preeclampsia have increased cardiovascular disease risk, however the mechanisms responsible for this association remain unclear. Microvascular damage sustained during a preeclamptic pregnancy may persist post‐partum, despite the remission of the clinical symptoms of preeclampsia. One putative mechanism contributing to persistent microvessel dysfunction in these women is increased vasoconstrictor sensitivity to endothelin‐1 (ET‐1), is a reduction endothelin‐1 type B receptor‐(ETBR) mediated. We hypothesized that 1) women who have had preeclampsia (PreEC) would have a greater vasoconstrictor sensitivity to exogenous ET‐1 administration compared to control women who had a normal pregnancy (HC), and that 2) this increased sensitivity would be due to a reduction in ETBR‐mediated dilation (protocol 1). We further hypothesized that ETBR‐blockade would attenuate endothelium‐dependent dilation to the agonist acetylcholine (Ach) in HC, but not PreEC (protocol 2). Ten PreEC (31±2 yrs, 7±2 mos. post‐partum) and 10 HC (28±2 yrs, 7±2 mos. post‐partum) participated. In protocol 1, 3 intradermal microdialysis fibers were placed in the forearm skin for the graded infusion of ET‐1 (10−20 – 10−8M) alone, ET‐1 + 500nM BQ‐123 for ETAR‐blockade, or the graded infusion of sarofotoxin 6c (S6c; 10−12 – 10−5M). In protocol 2, 2 fibers were placed for the graded infusion of ACh (10−7 – 102 mM) alone, and ACh + 500nM BQ‐788 for ETBR‐blockade. In both protocols, red cell flux was measured over each site by laser‐Doppler flowmetry (LDF). Cutaneous vascular conductance was calculated (CVC=LDF/MAP) and normalized to baseline (%CVCbase; protocol 1) or maximal (%CVCmax, 28mM SNP and local heat, 43°C; protocol 2). PreEC had augmented vasoconstrictor sensitivity to ET‐1 (PreEC −16.0±0.3 vs. HC −13.7±0.4 logEC50, P=0.01). Protocol 1: PreEC demonstrated a reduced dilation response to selective ETBR stimulation with ET‐1 (ET+BQ‐123: PreEC 130±22 vs. HC 290±77 %CVCbase; P=0.04), and reduced dilator sensitivity to the ETBR selective agonist S6c (PreEC −8.0±0.4 vs HC −8.9±0.7 logEC50; P=0.04). Protocol 2: PreEC had attenuated endothelium‐dependent dilation (PreEC 68±5 vs. HC 92±2 %CVCmax; P<0.01). ETBR inhibition attenuated the microvascular dilation response to ACh in HC (ACh alone 92±2 vs. ACh+BQ‐788 81±2 %CVCmax; P<0.01) but not in PreEC (ACh alone 68±5 vs. ACh+BQ‐788 74±3 %CVCmax; P=0.28). Women who have had preeclampsia demonstrate augmented vasoconstrictor sensitivity to ET‐1, mediated by a reduced ETBR‐dependent dilation response. Furthermore, attenuated ETBR‐mediated dilation contributes to diminished endothelial function which persists post‐partum in women who have had preeclampsia.Support or Funding InformationNIH F32 HL129677‐02 (Stanhewicz), R01 HL093238‐06 (Alexander)