| First Author | Cowburn AS | Year | 2016 |
| Journal | Proc Natl Acad Sci U S A | Volume | 113 |
| Issue | 31 | Pages | 8801-6 |
| PubMed ID | 27432976 | Mgi Jnum | J:234394 |
| Mgi Id | MGI:5789971 | Doi | 10.1073/pnas.1602978113 |
| Citation | Cowburn AS, et al. (2016) HIF2alpha-arginase axis is essential for the development of pulmonary hypertension. Proc Natl Acad Sci U S A 113(31):8801-6 |
| abstractText | Hypoxic pulmonary vasoconstriction is correlated with pulmonary vascular remodeling. The hypoxia-inducible transcription factors (HIFs) HIF-1alpha and HIF-2alpha are known to contribute to the process of hypoxic pulmonary vascular remodeling; however, the specific role of pulmonary endothelial HIF expression in this process, and in the physiological process of vasoconstriction in response to hypoxia, remains unclear. Here we show that pulmonary endothelial HIF-2alpha is a critical regulator of hypoxia-induced pulmonary arterial hypertension. The rise in right ventricular systolic pressure (RVSP) normally observed following chronic hypoxic exposure was absent in mice with pulmonary endothelial HIF-2alpha deletion. The RVSP of mice lacking HIF-2alpha in pulmonary endothelium after exposure to hypoxia was not significantly different from normoxic WT mice and much lower than the RVSP values seen in WT littermate controls and mice with pulmonary endothelial deletion of HIF-1alpha exposed to hypoxia. Endothelial HIF-2alpha deletion also protected mice from hypoxia remodeling. Pulmonary endothelial deletion of arginase-1, a downstream target of HIF-2alpha, likewise attenuated many of the pathophysiological symptoms associated with hypoxic pulmonary hypertension. We propose a mechanism whereby chronic hypoxia enhances HIF-2alpha stability, which causes increased arginase expression and dysregulates normal vascular NO homeostasis. These data offer new insight into the role of pulmonary endothelial HIF-2alpha in regulating the pulmonary vascular response to hypoxia. |
