| First Author | Frump AL | Year | 2018 |
| Journal | Am J Respir Cell Mol Biol | Volume | 59 |
| Issue | 1 | Pages | 114-126 |
| PubMed ID | 29394091 | Mgi Jnum | J:276811 |
| Mgi Id | MGI:6316745 | Doi | 10.1165/rcmb.2017-0167OC |
| Citation | Frump AL, et al. (2018) Hypoxia Upregulates Estrogen Receptor beta in Pulmonary Artery Endothelial Cells in a HIF-1alpha-Dependent Manner. Am J Respir Cell Mol Biol 59(1):114-126 |
| abstractText | 17beta-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 1alpha (HIF-1alpha)-dependent increases in ERbeta expression. Sprague-Dawley rats and ERalpha or ERbeta 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 ERbeta, but not ERalpha, in lungs from HPH rats as well as in rat and human PAECs. ERbeta mRNA time dependently increased in PAECs exposed to hypoxia. Normoxic HIF-1alpha/HIF-2alpha stabilization increased PAEC ERbeta, whereas HIF-1alpha knockdown decreased ERbeta abundance in hypoxic PAECs. In turn, ERbeta knockdown in hypoxic PAECs increased HIF-2alpha expression, suggesting a hypoxia-sensitive feedback mechanism. ERbeta knockdown in hypoxic PAECs also decreased expression of the HIF inhibitor prolyl hydroxylase 2 (PHD2), whereas ERbeta activation increased PHD2 and decreased both HIF-1alpha and HIF-2alpha, suggesting that ERbeta regulates the PHD2/HIF-1alpha/HIF-2alpha axis during hypoxia. Whereas hypoxic wild-type or ERalpha knockout mice treated with E2 demonstrated less pulmonary vascular remodeling and decreased HIF-1alpha after hypoxia compared with untreated hypoxic mice, ERbeta knockout mice exhibited increased HIF-2alpha and an attenuated response to E2 during hypoxia. Taken together, our results demonstrate a novel and potentially therapeutically targetable mechanism whereby hypoxia, via HIF-1alpha, increases ERbeta expression and the E2-ERbeta axis targets PHD2, HIF-1alpha, and HIF-2alpha to attenuate HPH development. |
