Rational Pulmonary arterial hypertension (PAH) is a rare but progressive and fatal disease caused by functional and structural changes in the pulmonary vasculature, which lead to an increase in pulmonary vascular resistance (PVR). Persistent hypoxia causes sustained pulmonary vasoconstriction (HPV) that may contributes to the elevated PVR in patients with pulmonary hypertension associated with hypoxia and lung diseases and in residents living in high altitude areas. Little is known about the molecular and cellular mechanisms, which underlie hypoxic pulmonary vasoconstriction and the development and progression of pulmonary hypertension.
Methods and Results To determine the functional relevance of hypoxia and hypoxia-inducible factors (HIFs) in the development of acute HPV, we compared high K+-induced increase in pulmonary arterial pressure (PAP) and acute alveolar hypoxia-mediated increase in PAP in isolated perfused and ventilated lungs between wild type (WT) and HIF1α or HIF2α conditional knockout (KO) mice. Conditional and inducible deletion of HIF1α or HIF2α in endothelial cells (HIF1αEC−/−, or HIF2αEC−/−), but not smooth muscle cells, dramatically protected mice from hypoxia-induced pulmonary hypertension. We analyzed the hypoxia-induced response in isolated lungs from WT and KO mice. Ventilation of lungs from mice with 1% O2 provoked a vasoconstrictor response and reached to the plateau within 4 min in both WT, HIF1αEC−/−, and HIF2αEC−/− mice. Normoxic vascular ton were not affected by deletion of HIF1α or HIF2α and there is no difference of vasoconstriction induced by high K+ between WT and KO mice.
Conclusion Our study has demonstrated that deletion of HIF1α or HIF2α in endothelial cells dramatically attenuate chronic hypoxia-induced pulmonary hypertension, but negligibly affect the acute hypoxia-induced pulmonary vasoconstriction. These results implicated that targets of endothelial HIFs signaling pathway may lead to novel therapeutic targets for chronic hypoxia-induced pulmonary hypertension but endothelial HIFs signaling are not involved in acute hypoxic pulmonary vasoconstriction.
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