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17[beta]-Estradiol Attenuates Hypoxic Pulmonary Hypertension via Estrogen Receptor-mediated Effects.
Lahm, Tim 1,2; Albrecht, Marjorie 1; Fisher, Amanda J. 3; Selej, Mona 1; Patel, Neel G. 1; Brown, Jordan A. 1; Justice, Matthew J. 1; Brown, Beth M. 1; Van Demark, Mary 1; Trulock, Kevin M. 1; Dieudonne, Dino 1; Reddy, Jagadeshwar G. 1; Presson, Robert G. 3,4; Petrache, Irina 1,2,4
[Article] American Journal of Respiratory & Critical Care Medicine. 185(9):965-980, May 1, 2012.

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Rationale: 17[beta]-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 [mu]g/kg/d) or vehicle. Subgroups were cotreated with pharmacologic ER-antagonist or with inhibitors of E2-metabolite conversion. Complementary studies were performed in rats cotreated with selective ER[alpha]- or ER[beta]-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 ER[beta] but not ER[alpha] lung vascular expression. Co-treatment with nonselective ER inhibitor or ER[alpha]-specific antagonist rendered hypoxic animals resistant to the beneficial effects of E2 on cardiopulmonary hemodynamics, whereas ER[alpha]- and ER[beta]-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 p27Kip1 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.

Conclusions: E2 attenuates hemodynamic and remodeling parameters in HPH in an ER-dependent manner, through direct antiproliferative mechanisms on vascular cells, which may provide novel nonhormonal therapeutic targets for HPH.