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Salutary Effects of Estrogen Receptor (ER)-a on the Pulmonary Vasculature in Experimental Pulmonary Hypertension (PH)

Andrea Frump

Bakhtiyor Yakubov

Lifan Zeng

Marjorie Albrecht

A Essex

Todd Cook


Amanda Fisher


D Martinez

JL Phillips

R Li

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Conference: 2018 PHA International PH Conference & Scientific Sessions

Release Date: 07.28.2018

Presentation Type: Abstracts

File Download: Conference 2018_1009

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2018 International PH Conference and Scientific SeAbstract presented at the 2018 International PH Conference and Scientific Sessions in Orlando, Fla., June 28-July 1, 2018.

Authors (Continued)

Sun X, Chesler NC, Lahm T

Background

Women are more prone to developing pulmonary arterial hypertension (PAH), but once affected also exhibit better survival. In the systemic vasculature, ERα exerts beneficial effects on endothelial cell function, while ERα loss-of-function mutations have been linked to cardiovascular disease. Effects of ERα on pulmonary artery endothelial cells (PAECs), on the other hand, are poorly defined. We hypothesize that ERα increases PAEC BMPR2 and apelin signaling, decreases PAEC apoptosis and attenuates pulmonary vascular remodeling.

Methods

PAECs were treated with 17β-estradiol (E2) or ERα-agonists PPT or BTPα (0.1 nM-100 nM; 6-24hrs) and apelin, BMPR2, phospho-Smad 1/5/8, and Id1 expression were analyzed (western blot). E2 or ERα-agonist effects on pro-apoptotic signaling were assessed by caspase-3/7 activity assay in PAECs treated with staurosporine (50-500 nM). PAEC tube formation was assessed by matrigel assay. For prevention studies, male and female Sprague-Dawley rats with sugen/hypoxia (SuHx)-PH were treated with E2 or PPT and female ERα knockout rats (generated by CRISPR-Cas) were exposed to 3 weeks hypoxia to induce PH. Additionally, monocrotaline (MCT)-PH rats were treated with E2 or PPT two weeks post MCT injection (rescue approach). Animals were assessed for hemodynamic alterations, pulmonary vascular remodeling (Verhoff-van Giessen stain), apoptotic signaling (TUNEL, cleaved caspase 3), BMPR2 signaling and apelin expression (whole lungs, western blot). p<0.05 by ANOVA was significant.

Results

Treatment with E2, PPT or BTPα increased BMPR2, Id1 and apelin expression and Smad1/5/8 phosphorylation in PAECs (p<0.05). PPT and BTPα attenuated staurosporine-induced increases in caspase-3/7 activity by 30% and E2 or PPT dose-dependently increased PAEC tube formation by 45% (p<0.05). In MCT rats treated with E2 or PPT, MCT-induced decreases in lung BMPR2 and apelin were rescued. PPT treatment attenuated SuHx-induced increases in lung cleaved caspase-3 at one week, and prevented pulmonary arterial remodeling at seven weeks (p<0.05). MCT rats treated with PPT exhibited a 58% decrease in total pulmonary resistance (TPR; surrogate for pulmonary vascular resistance; p<0.05), whereas availability of ERα in control female rats prevented the near doubling of arterial elastance and TPR with hypoxia observed in female ERα KO rats (p<0.05), suggesting increased RV afterload is attenuated by ERα.

Conclusions

We identified a novel mechanism of action of ERα leading to attenuation of pro-apoptotic signaling and up-regulation of BMPR2 and apelin in cultured PAECs and in vivo. Compared to broadly targeting estrogen in PAH, selectively activating ERα signaling may allow for a more precise strategy to harness protective estrogenic effects, maximizing benefit while avoiding detriment.