Altered hypoxia‐inducible factor–1 α (HIF‐1 α ) signaling contributes to impaired angiogenesis in fetal lambs with persistent pulmonary hypertension of the newborn (PPHN)

Previous studies in adult pulmonary hypertension reported that increased hypoxia‐inducible factor–1 α ( HIF ‐1 α ) signaling contributes to pulmonary vascular remodeling. However, alterations in endothelial HIF ‐1 α signaling and its contribution to impaired angiogenesis in persistent pulmonary hypertension of the newborn ( PPHN ) remain unclear. We investigated the hypothesis that HIF ‐1 α levels are increased in lung endothelial cells in PPHN and contribute to impaired angiogenesis function. We examined HIF ‐1 α expression and promoter activity in the isolated pulmonary artery endothelial cells ( PAEC ) from fetal lambs with or without PPHN induced by prenatal ductus arteriosus constriction. We measured the levels of HIF ‐1 α downstream targets, vascular endothelial growth factor ( VEGF ) and glycolytic protein, hexokinase 2 (Hek‐2) in PAEC from PPHN , and control lambs. We examined the effect of small interfering‐ RNA (si RNA ) mediated knockdown of native HIF ‐1 α on VEGF expression and in vitro angiogenesis function of PPHN ‐ PAEC . HIF ‐1 α protein levels were higher in the isolated PAEC from PPHN ‐lambs compared to controls. HIF ‐1 α promoter activity and Hek‐2 protein levels were higher in PPHN . VEGF protein levels and in vitro angiogenesis function were decreased in PAEC from PPHN lambs. HIF ‐1 α silencing significantly increased the expression of VEGF and improved the angiogenesis function of PPHN PAEC . Aberrant HIF ‐1 α signaling contributes to endothelial dysfunction and decreased angiogenesis in PPHN .