Hypoxia upregulates estrogen receptor β in pulmonary artery endothelial cells in α HIF-1a-dependent manner

Andrea L. Frump, Mona Selej, Jordan A. Wood, Marjorie Albrecht, Bakhtiyor Yakubov, Irina Petrache, Tim Lahm

Research output: Contribution to journalArticle

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Abstract

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 ERb expression. Sprague-Dawley rats and ERa or ERb 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 ERb, but not ERa, in lungs from HPH rats as well as in rat and human PAECs. ERb mRNA time dependently increased in PAECs exposed to hypoxia. Normoxic HIF-1α/HIF-2α stabilization increased PAEC ERb, whereas HIF-1α knockdown decreased ERb abundance in hypoxic PAECs. In turn, ERb knockdown in hypoxic PAECs increased HIF-2α expression, suggesting a hypoxia-sensitive feedback mechanism. ERb knockdown in hypoxic PAECs also decreased expression of the HIF inhibitor prolyl hydroxylase 2 (PHD2), whereas ERb activation increased PHD2 and decreased bothHIF-1α and HIF-2α, suggesting that ERb regulates the PHD2/HIF-1α/HIF-2α axis during hypoxia. Whereas hypoxic wild-type or ERa knockout mice treated with E2 demonstrated less pulmonary vascular remodeling and decreased HIF-1α after hypoxia compared with untreated hypoxic mice, ERb 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 mechanismwhereby hypoxia, via HIF-1α, increases ERb expression and the E2-ERb axis targets PHD2, HIF-1α, and HIF-2α to attenuate HPH development.

Original languageEnglish (US)
Pages (from-to)114-126
Number of pages13
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume59
Issue number1
DOIs
StatePublished - Jul 1 2018

Fingerprint

Hypoxia-Inducible Factor 1
Endothelial cells
Estrogen Receptors
Pulmonary Artery
Up-Regulation
Endothelial Cells
Rats
Pulmonary Hypertension
Hypoxia-Inducible Factor-Proline Dioxygenases
Prolyl-Hydroxylase Inhibitors
Knockout Mice
Prolyl Hydroxylases
Hypoxia
Cell proliferation
Estradiol
Stabilization
Chemical activation
Lung
Feedback
Messenger RNA

Keywords

  • 17βestradiol
  • Hypoxia-inducible factor 1α
  • Hypoxia-inducible factor 2α
  • Prolyl hydroxylase 2
  • Pulmonary hypertension

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

Hypoxia upregulates estrogen receptor β in pulmonary artery endothelial cells in α HIF-1a-dependent manner. / Frump, Andrea L.; Selej, Mona; Wood, Jordan A.; Albrecht, Marjorie; Yakubov, Bakhtiyor; Petrache, Irina; Lahm, Tim.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 59, No. 1, 01.07.2018, p. 114-126.

Research output: Contribution to journalArticle

Frump, Andrea L. ; Selej, Mona ; Wood, Jordan A. ; Albrecht, Marjorie ; Yakubov, Bakhtiyor ; Petrache, Irina ; Lahm, Tim. / Hypoxia upregulates estrogen receptor β in pulmonary artery endothelial cells in α HIF-1a-dependent manner. In: American Journal of Respiratory Cell and Molecular Biology. 2018 ; Vol. 59, No. 1. pp. 114-126.
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AB - 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 ERb expression. Sprague-Dawley rats and ERa or ERb 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 ERb, but not ERa, in lungs from HPH rats as well as in rat and human PAECs. ERb mRNA time dependently increased in PAECs exposed to hypoxia. Normoxic HIF-1α/HIF-2α stabilization increased PAEC ERb, whereas HIF-1α knockdown decreased ERb abundance in hypoxic PAECs. In turn, ERb knockdown in hypoxic PAECs increased HIF-2α expression, suggesting a hypoxia-sensitive feedback mechanism. ERb knockdown in hypoxic PAECs also decreased expression of the HIF inhibitor prolyl hydroxylase 2 (PHD2), whereas ERb activation increased PHD2 and decreased bothHIF-1α and HIF-2α, suggesting that ERb regulates the PHD2/HIF-1α/HIF-2α axis during hypoxia. Whereas hypoxic wild-type or ERa knockout mice treated with E2 demonstrated less pulmonary vascular remodeling and decreased HIF-1α after hypoxia compared with untreated hypoxic mice, ERb 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 mechanismwhereby hypoxia, via HIF-1α, increases ERb expression and the E2-ERb axis targets PHD2, HIF-1α, and HIF-2α to attenuate HPH development.

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