Endothelial PI3K-C2α, a class II PI3K, has an essential role in angiogenesis and vascular barrier function

Although type I phosphatidylinositol 3-kinases (PI3Ks) are well studied signaling proteins, the functions of other PI3Ks are more enigmatic. Kazuaki Yoshioka et al. find that the type II PI3K-2α isoform regulates endosomal trafficking and cell signaling in endothelial cells. Angiogenic and vascular permeability responses are attenuated in mice lacking PI3K-2α, pointing to this enzyme as a potential target for treating vascular disease. The class II α-isoform of phosphatidylinositol 3-kinase (PI3K-C2α) is localized in endosomes, the trans-Golgi network and clathrin-coated vesicles; however, its functional role is not well understood. Global or endothelial-cell–specific deficiency of PI3K-C2α resulted in embryonic lethality caused by defects in sprouting angiogenesis and vascular maturation. PI3K-C2α knockdown in endothelial cells resulted in a decrease in the number of PI3-phosphate–enriched endosomes, impaired endosomal trafficking, defective delivery of VE-cadherin to endothelial cell junctions and defective junction assembly. PI3K-C2α knockdown also impaired endothelial cell signaling, including vascular endothelial growth factor receptor internalization and endosomal RhoA activation. Together, the effects of PI3K-C2α knockdown led to defective endothelial cell migration, proliferation, tube formation and barrier integrity. Endothelial PI3K-C2α deficiency in vivo suppressed postischemic and tumor angiogenesis and diminished vascular barrier function with a greatly augmented susceptibility to anaphylaxis and a higher incidence of dissecting aortic aneurysm formation in response to angiotensin II infusion. Thus, PI3K-C2α has a crucial role in vascular formation and barrier integrity and represents a new therapeutic target for vascular disease.