Vascular HIF2 Signaling Prevents Cardiomegaly, Alveolar Congestion, and Capillary Remodeling During Chronic Hypoxia

BACKGROUND: Hypoxia is associated with the onset of cardiovascular diseases including cardiac hypertrophy and pulmonary hypertension. HIF2 (hypoxia inducible factor 2) signaling in the endothelium mediates pulmonary arterial remodeling and subsequent elevation of the right ventricular systolic pressure during chronic hypoxia. Thus, novel therapeutic opportunities for pulmonary hypertension based on specific HIF2 inhibitors have been proposed. Nevertheless, HIF2 relevance beyond the pulmonary endothelium or in the cardiac adaptation to hypoxia remains elusive. Wt1 (Wilms tumor 1) lineage contributes to the heart and lung vascular compartments, including pericytes, endothelial cells, and smooth muscle cells. METHODS: Here, we describe the response to chronic hypoxia of a novel HIF2 mutant mouse model in the Wt1 lineage ( Hif2/Wt1 cKO [conditional knockout]), characterizing structural and functional aspects of the heart and lungs by means of classical histology, immunohistochemistry, flow cytometry, echocardiography, and lung ultrasound analysis. RESULTS: Hif2/Wt1 cKO is protected against pulmonary remodeling and increased right ventricular systolic pressure induced by hypoxia, but displays alveolar congestion, inflammation, and hemorrhages associated with microvascular instability. Furthermore, lack of HIF2 in the Wt1 lineage leads to cardiomegaly, capillary remodeling, right and left ventricular hypertrophy, systolic dysfunction, and left ventricular dilation, suggesting pulmonary-independent cardiac direct roles of HIF2 in hypoxia. These structural defects are partially restored upon reoxygenation, while cardiac functional parameters remain altered. CONCLUSIONS: Our results indicate that cardiopulmonary HIF2 signaling prevents excessive vascular proliferation during chronic hypoxia and define novel protective roles of HIF2 to warrant stable microvasculature and organ function.