title: Endothelial PI3K-C2α, a class II PI3K, has an essential role in angiogenesis and vascular barrier function.
abstract: 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.
authors.affiliation: Department of Physiology, Kanazawa University School of Medicine, Kanazawa, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Yoshioka
authors.forename: Kotaro
authors.initials: K
authors.lastname: Yoshida
authors.forename: Hong
authors.initials: H
authors.lastname: Cui
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Wakayama
authors.forename: Noriko
authors.initials: N
authors.lastname: Takuwa
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Wa
authors.initials: W
authors.lastname: Du
authors.forename: Xun
authors.initials: X
authors.lastname: Qi
authors.forename: Ken
authors.initials: K
authors.lastname: Asanuma
authors.forename: Kazushi
authors.initials: K
authors.lastname: Sugihara
authors.forename: Sho
authors.initials: S
authors.lastname: Aki
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Miyazawa
authors.forename: Kuntal
authors.initials: K
authors.lastname: Biswas
authors.forename: Chisa
authors.initials: C
authors.lastname: Nagakura
authors.forename: Masaya
authors.initials: M
authors.lastname: Ueno
authors.forename: Shoichi
authors.initials: S
authors.lastname: Iseki
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schwartz
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okamoto
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasaki
authors.forename: Osamu
authors.initials: O
authors.lastname: Matsui
authors.forename: Masahide
authors.initials: M
authors.lastname: Asano
authors.forename: Ralf H
authors.initials: RH
authors.lastname: Adams
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takakura
authors.forename: Yoh
authors.initials: Y
authors.lastname: Takuwa
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015824:Blood-Air Barrier / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D022163:Clathrin-Coated Vesicles / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D021601:trans-Golgi Network / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D000804:Angiotensin II; D015703:Antigens, CD; D015820:Cadherins; D019869:Phosphatidylinositol 3-Kinases; D034741:RNA, Small Interfering; D040262:Receptors, Vascular Endothelial Growth Factor; D020742:rhoA GTP-Binding Protein; D000099152:Cadherin 5; C546635:Pik3c2a protein, mouse