Placenta growth factor mediates angiogenesis in hypoxic pulmonary hypertension

Our previous studies have proved that hypoxia enhances the 15-lipoxygenase (15-LO) expression and increases endogenous 15-hydroxyeicosatetraenoic acid (15-HETE) production to promote pulmonary vascular remodeling and angiogenesis, while the mechanisms of how hypoxia regulates 15-LO expression in endothelium is still unknown. As placenta growth factor (PlGF) promotes pathological angiogenesis by acting on the growth, migration and survival of endothelial cells, there may be some connections between PlGF and 15-LO in hypoxia induced endothelial cells proliferation. In this study, we performed immunohistochemistry, pulmonary artery endothelial cells migration and bromodeoxyuridine incorporation to determine the role of PlGF in pulmonary remodeling induced by hypoxia. Our results showed that hypoxia up-regulated PlGF expression, which was mediated by 15-LO/15-HETE pathway. Furthermore, we found that PlGF had a positive feedback regulation with 15-LO expression and 15-HETE generation. The interaction in hypoxia between 15-HETE and PlGF created a PlGF-15-LO-15-HETE loop, leading to endothelial dysfunction. Thus, these findings suggest a new therapeutic agent in combination with the blockade of PlGF as well as 15-LO in hypoxic pulmonary hypertension.