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Hypoxia Upregulates Estrogen Receptor ? in Pulmonary Artery Endothelial Cells in a HIF-1?-Dependent Manner.

ABSTRACT: 17?-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 1? (HIF-1?)-dependent increases in ER? expression. Sprague-Dawley rats and ER? or ER? 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 ER?, but not ER?, in lungs from HPH rats as well as in rat and human PAECs. ER? mRNA time dependently increased in PAECs exposed to hypoxia. Normoxic HIF-1?/HIF-2? stabilization increased PAEC ER?, whereas HIF-1? knockdown decreased ER? abundance in hypoxic PAECs. In turn, ER? knockdown in hypoxic PAECs increased HIF-2? expression, suggesting a hypoxia-sensitive feedback mechanism. ER? knockdown in hypoxic PAECs also decreased expression of the HIF inhibitor prolyl hydroxylase 2 (PHD2), whereas ER? activation increased PHD2 and decreased both HIF-1? and HIF-2?, suggesting that ER? regulates the PHD2/HIF-1?/HIF-2? axis during hypoxia. Whereas hypoxic wild-type or ER? knockout mice treated with E2 demonstrated less pulmonary vascular remodeling and decreased HIF-1? after hypoxia compared with untreated hypoxic mice, ER? knockout mice exhibited increased HIF-2? and an attenuated response to E2 during hypoxia. Taken together, our results demonstrate a novel and potentially therapeutically targetable mechanism whereby hypoxia, via HIF-1?, increases ER? expression and the E2-ER? axis targets PHD2, HIF-1?, and HIF-2? to attenuate HPH development.

SUBMITTER: Frump AL

PROVIDER: S-EPMC6039879 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

Frump Andrea L AL Selej Mona M Wood Jordan A JA Albrecht Marjorie M Yakubov Bakhtiyor B Petrache Irina I Lahm Tim T

American journal of respiratory cell and molecular biology 20180701 1

17β-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 ...[more]

PMID: 29394091

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Project description:BackgroundHypoxia naturally happens in embryogenesis and thus serves as an important environmental factor affecting embryo development. Hif-1α, an essential hypoxia response factor, was mostly considered to mediate or synergistically regulate the effect of hypoxia on stem cells. However, the function and relationship of hypoxia and Hif-1α in regulating mesendoderm differentiation remains controversial.ResultsWe here discovered that hypoxia dramatically suppressed the mesendoderm differentiation and promoted the ectoderm differentiation of mouse embryonic stem cells (mESCs). However, hypoxia treatment after mesendoderm was established promoted the downstream differentiation of mesendoderm-derived lineages. These effects of hypoxia were mediated by the repression of the Wnt/β-Catenin pathway and the Wnt/β-Catenin pathway was at least partially regulated by the Akt/Gsk3β axis. Blocking the Wnt/β-Catenin pathway under normoxia using IWP2 mimicked the effects of hypoxia while activating the Wnt/β-Catenin pathway with CHIR99021 fully rescued the mesendoderm differentiation suppression caused by hypoxia. Unexpectedly, Hif-1α overexpression, in contrast to hypoxia, promoted mesendoderm differentiation and suppressed ectoderm differentiation. Knockdown of Hif-1α under normoxia and hypoxia both inhibited the mesendoderm differentiation. Moreover, hypoxia even suppressed the mesendoderm differentiation of Hif-1α knockdown mESCs, further implying that the effects of hypoxia on the mesendoderm differentiation were Hif-1α independent. Consistently, the Wnt/β-Catenin pathway was enhanced by Hif-1α overexpression and inhibited by Hif-1α knockdown. As shown by RNA-seq, unlike hypoxia, the effect of Hif-1α was relatively mild and selectively regulated part of hypoxia response genes, which fine-tuned the effect of hypoxia on mESC differentiation.ConclusionsThis study revealed that hypoxia is fine-tuned by Hif-1α and regulates the mesendoderm and ectoderm differentiation by manipulating the Wnt/β-Catenin pathway, which contributed to the understanding of hypoxia-mediated regulation of development.

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Hypoxia Upregulates Estrogen Receptor ? in Pulmonary Artery Endothelial Cells in a HIF-1?-Dependent Manner.

Publications

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

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