17β-Estradiol attenuates hypoxic pulmonary hypertension via estrogen receptor-mediated effects

Tim Lahm, Marjorie Albrecht, Amanda J. Fisher, Mona Selej, Neel G. Patel, Jordan A. Brown, Matthew J. Justice, M. Beth Brown, Mary Van Demark, Kevin M. Trulock, Dino Dieudonne, Jagadeshwar G. Reddy, Robert G. Presson, Irina Petrache

Research output: Contribution to journalArticle

98 Scopus citations

Abstract

Rationale: 17β-Estradiol (E2) attenuates hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension (HPH) through an unknown mechanism that may involve estrogen receptors (ER) or E2 conversion to catecholestradiols and methoxyestradiols with previously unrecognized effects on cardiopulmonary vascular remodeling. Objectives: To determine the mechanism by which E2 exerts protective effects in HPH. Methods: Male rats were exposed to hypobaric hypoxia while treated with E2 (75 μg/kg/d) or vehicle. Subgroups were cotreated with pharmacologic ER- antagonistor with inhibitors of E2-metabolite conversion. Complementary studies were performed in rats cotreated with selective ERα- or ERβ-antagonist. Hemodynamic and pulmonary artery (PA) and right ventricular (RV) remodeling parameters, including cell proliferation, cell cycle, and autophagy, were measured in vivo and in cultured primary rat PA endothelial cells. Measurements and Main Results: E2 significantly attenuated HPH endpoints. Hypoxia increased ERβ but not ERα lung vascular expression. Co-treatment with nonselective ER inhibitor or ERα-specific antagonist rendered hypoxic animals resistant to the beneficial effects of E2 on cardiopulmonary hemodynamics, whereas ERα- and ERβ-specific antagonists opposed the remodeling effects of E2. In contrast, inhibition of E2-metabolite conversion did not abolish E2 protection. E2- treated hypoxic animals exhibited reduced ERK1/2 activation and increased expression of cell-cycle inhibitor p27 Kip1 in lungs and RV, with up-regulation of lung autophagy. E2-induced signaling was recapitulated in hypoxic but not normoxic endothelial cells, and was associated with decreased vascular endothelial growth factor secretion and cell proliferation.

Original languageEnglish (US)
Pages (from-to)965-980
Number of pages16
JournalAmerican journal of respiratory and critical care medicine
Volume185
Issue number9
DOIs
StatePublished - May 1 2012

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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    Lahm, T., Albrecht, M., Fisher, A. J., Selej, M., Patel, N. G., Brown, J. A., Justice, M. J., Brown, M. B., Van Demark, M., Trulock, K. M., Dieudonne, D., Reddy, J. G., Presson, R. G., & Petrache, I. (2012). 17β-Estradiol attenuates hypoxic pulmonary hypertension via estrogen receptor-mediated effects. American journal of respiratory and critical care medicine, 185(9), 965-980. https://doi.org/10.1164/rccm.201107-1293OC