12-lipoxygenase and 12-hydroxyeicosatetraenoic acid regulate hypoxic angiogenesis and survival of pulmonary artery endothelial cells via PI3K/Akt pathway

Abstract

Dysfunction and injury of endothelial cells play critical roles in pulmonary arterial hypertension, including aberrant proliferation, suppressed apoptosis, and excessive angiogenesis. The 12-lipoxygenase and 12-hydroxyeicosatetraenoic acid pathway, which has been considered as a crucial mediator, elevates pulmonary vascular resistance and pulmonary arterial pressure. However, the mechanisms underlying the bioactivity of 12-hydroxyeicosatetraenoic acid in pulmonary vasculature, especially in endothelial cells, are still elusive. Thus we aim to determine the key role of 12-lipoxygenase/12-hydroxyeicosatetraenoic acid in angiogenesis and survival of pulmonary artery endothelial cells and ascertain the signaling pathways participating in the pathological process. Here we establish that hypoxia increases the formation of endogenous 12-hydroxyeicosatetraenoic acid through stimulation of 12-lipoxygenase. Furthermore, we put forward new information that 12-hydroxyeicosatetraenoic acid promotes endothelial cell migration and tube formation, whereas it inhibits the serum deprivation-induced apoptotic responses under hypoxia. Particularly, the regulatory effects of 12-lipoxygenase/12-hydroxyeicosatetraenoic acid on pulmonary artery endothelial cells, at least in part, depend on phosphatidylinositol 3-kinase (PI3K)/Akt signaling activation. Taken together, these results may have significant implications for understanding of pulmonary hypertension and offer a potential therapeutic concept focusing on the 12-lipoxygenase/12-hydroxyeicosatetraenoic acid signaling system.