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Protective Effects of 17-Beta Estradiol (E2) in Hypoxic Pulmonary Hypertension are Mediated by Estrogen Receptors Alpha and Beta

Tim Lahm

Marjorie Albrecht

A. J. Fisher

M Selej

N.G. Patel

J.A. Brown

M.J. Justice

K.M. Trulock

D Dieudonne


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Conference: 2012 International PHA Conference and Scientific Sessions

Release Date: 06.22.2012

Presentation Type: Abstracts

BACKGROUND: E2 attenuates hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension (HPH) through an unknown mechanism that may involve estrogen receptors (ER) or E2 conversion to catechol- and methoxyestradiols with previously unrecognized effects on cardiopulmonary vascular remodeling. We sought 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 micrograms/kg/day) or vehicle. Subgroups were co-treated with pharmacological ER-antagonist, or with inhibitors of E2-metabolite conversion. Complementary studies were performed in rats co-treated 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 (PAECs).

RESULTS: E2 significantly attenuated HPH endpoints. Hypoxia increased ERβ, but not ERα lung vascular expression. Co-treatment with non-selective ER-inhibitor or ERα-specific antagonist rendered hypoxic animals resistant to E2’s beneficial effects on cardiopulmonary hemodynamics, whereas both ERα- and ERβ-specific antagonists opposed E2’s remodeling effects. 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 upregulation of lung autophagy. E2-induced signaling was recapitulated in hypoxic, but not normoxic PAECs, and was associated with decreased VEGF secretion and cell proliferation. E2 effects on hypoxic PAECs were attenuated with ERα-selective as well as with ERβ-selective antagonist.

CONCLUSIONS: E2 attenuates hemodynamic and remodeling parameters in HPH in an ER-dependent manner. Both, ERα and ERβ mediate protective effects of E2 in HPH. E2 exerts direct antiproliferative mechanisms on vascular cells, which may provide novel non-hormonal therapeutic targets for HPH.

FUNDING: ATS/PHA/Pfizer Fellowship in PAH Research, Dept of Veterans Affairs, IUPUI RSFG.