Endothelial PI3K-C2α, a class II PI3K, has an essential role in angiogenesis and vascular barrier function
Copyright policy )Endothelial PI3K-C2α, a class II PI3K, has an essential role in angiogenesis and vascular barrier function
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.
- Japan Atomic Energy Agency Japan
- University of Münster Germany
- Max Planck Society Germany
- Osaka University Japan
- Tohoku University Japan
Mice, Knockout, Blood-Air Barrier, Angiotensin II, Neovascularization, Physiologic, Clathrin-Coated Vesicles, Cadherins, Mice, Phosphatidylinositol 3-Kinases, Receptors, Vascular Endothelial Growth Factor, Antigens, CD, Cell Movement, Cell Adhesion, Human Umbilical Vein Endothelial Cells, Animals, Humans, RNA Interference, RNA, Small Interfering, Cells, Cultured, Cell Proliferation, Signal Transduction
Mice, Knockout, Blood-Air Barrier, Angiotensin II, Neovascularization, Physiologic, Clathrin-Coated Vesicles, Cadherins, Mice, Phosphatidylinositol 3-Kinases, Receptors, Vascular Endothelial Growth Factor, Antigens, CD, Cell Movement, Cell Adhesion, Human Umbilical Vein Endothelial Cells, Animals, Humans, RNA Interference, RNA, Small Interfering, Cells, Cultured, Cell Proliferation, Signal Transduction
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