HIF2α-arginase axis is essential for the development of pulmonary hypertension.
Hypoxic pulmonary vasoconstriction is correlated with pulmonary vascular remodeling. The hypoxia-inducible transcription factors (HIFs) HIF-1α and HIF-2α 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-2α 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-2α deletion. The RVSP of mice lacking HIF-2α 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-1α exposed to hypoxia. Endothelial HIF-2α deletion also protected mice from hypoxia remodeling. Pulmonary endothelial deletion of arginase-1, a downstream target of HIF-2α, likewise attenuated many of the pathophysiological symptoms associated with hypoxic pulmonary hypertension. We propose a mechanism whereby chronic hypoxia enhances HIF-2α stability, which causes increased arginase expression and dysregulates normal vascular NO homeostasis. These data offer new insight into the role of pulmonary endothelial HIF-2α in regulating the pulmonary vascular response to hypoxia.
['Cowburn|Andrew S|AS|', 'Crosby|Alexi|A|', 'Macias|David|D|', 'Branco|Cristina|C|', 'Colaço|Renato D D R|RD|', 'Southwood|Mark|M|', 'Toshner|Mark|M|', 'Crotty Alexander|Laura E|LE|', 'Morrell|Nicholas W|NW|', 'Chilvers|Edwin R|ER|', 'Johnson|Randall S|RS|']
D000818:Animals D001119:Arginase D051792:Basic Helix-Loop-Helix Transcription Factors D015687:Cell Hypoxia D002478:Cells, Cultured D004730:Endothelium, Vascular D006801:Humans D006976:Hypertension, Pulmonary D000860:Hypoxia D051795:Hypoxia-Inducible Factor 1, alpha Subunit D008297:Male D008810:Mice, Inbred C57BL D018345:Mice, Knockout D008822:Mice, Transgenic D009569:Nitric Oxide D016278:Ventricular Function, Right D017725:Ventricular Pressure
pulmonary hypertension HIF hypoxia