Hypoxia Upregulates Estrogen Receptor β in Pulmonary Artery Endothelial Cells in a HIF-1α-Dependent Manner

dc.contributor.authorFrump, Andrea L.
dc.contributor.authorSelej, Mona
dc.contributor.authorWood, Jordan A.
dc.contributor.authorAlbrecht, Marjorie
dc.contributor.authorYakubov, Bakhtiyor
dc.contributor.authorPetrache, Irina
dc.contributor.authorLahm, Tim
dc.contributor.departmentCellular & Integrative Physiology, IU School of Medicineen_US
dc.date.accessioned2019-09-06T15:55:29Z
dc.date.available2019-09-06T15:55:29Z
dc.date.issued2018-07
dc.description.abstract17β-Estradiol (E2) attenuates hypoxia-induced pulmonary hypertension (HPH) through estrogen receptor (ER)-dependent effects, including inhibition of hypoxia-induced endothelial cell proliferation; however, the mechanisms responsible for this remain unknown. We hypothesized that the protective effects of E2 in HPH are mediated through hypoxia-inducible factor 1α (HIF-1α)-dependent increases in ERβ expression. Sprague-Dawley rats and ERα or ERβ knockout mice were exposed to hypobaric hypoxia for 2-3 weeks. The effects of hypoxia were also studied in primary rat or human pulmonary artery endothelial cells (PAECs). Hypoxia increased expression of ERβ, but not ERα, in lungs from HPH rats as well as in rat and human PAECs. ERβ mRNA time dependently increased in PAECs exposed to hypoxia. Normoxic HIF-1α/HIF-2α stabilization increased PAEC ERβ, whereas HIF-1α knockdown decreased ERβ abundance in hypoxic PAECs. In turn, ERβ knockdown in hypoxic PAECs increased HIF-2α expression, suggesting a hypoxia-sensitive feedback mechanism. ERβ knockdown in hypoxic PAECs also decreased expression of the HIF inhibitor prolyl hydroxylase 2 (PHD2), whereas ERβ activation increased PHD2 and decreased both HIF-1α and HIF-2α, suggesting that ERβ regulates the PHD2/HIF-1α/HIF-2α axis during hypoxia. Whereas hypoxic wild-type or ERα knockout mice treated with E2 demonstrated less pulmonary vascular remodeling and decreased HIF-1α after hypoxia compared with untreated hypoxic mice, ERβ knockout mice exhibited increased HIF-2α and an attenuated response to E2 during hypoxia. Taken together, our results demonstrate a novel and potentially therapeutically targetable mechanism whereby hypoxia, via HIF-1α, increases ERβ expression and the E2-ERβ axis targets PHD2, HIF-1α, and HIF-2α to attenuate HPH development.en_US
dc.identifier.citationFrump, A. L., Selej, M., Wood, J. A., Albrecht, M., Yakubov, B., Petrache, I., & Lahm, T. (2018). Hypoxia Upregulates Estrogen Receptor β in Pulmonary Artery Endothelial Cells in a HIF-1α-Dependent Manner. American journal of respiratory cell and molecular biology, 59(1), 114–126. doi:10.1165/rcmb.2017-0167OCen_US
dc.identifier.urihttps://hdl.handle.net/1805/20845
dc.language.isoen_USen_US
dc.publisherAmerican Thoracic Societyen_US
dc.relation.isversionof10.1165/rcmb.2017-0167OCen_US
dc.relation.journalAmerican Journal of Respiratory Cell and Molecular Biologyen_US
dc.rightsPublisher Policyen_US
dc.sourcePMCen_US
dc.subjectHypoxia-inducible factor 1αen_US
dc.subjectHypoxia-inducible factor 2αen_US
dc.subjectPulmonary hypertensionen_US
dc.subjectProlyl hydroxylase 2en_US
dc.subject17β-estradiolen_US
dc.titleHypoxia Upregulates Estrogen Receptor β in Pulmonary Artery Endothelial Cells in a HIF-1α-Dependent Manneren_US
dc.typeArticleen_US
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