@article{603270bf963345fea9226dd90f7513b0,
title = "Endothelial PI3K-C2α, a class II PI3K, has an essential role in angiogenesis and vascular barrier function",
abstract = "The class II a-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.",
author = "Kazuaki Yoshioka and Kotaro Yoshida and Hong Cui and Tomohiko Wakayama and Noriko Takuwa and Yasuo Okamoto and Wa Du and Xun Qi and Ken Asanuma and Kazushi Sugihara and Sho Aki and Hidekazu Miyazawa and Kuntal Biswas and Chisa Nagakura and Masaya Ueno and Shoichi Iseki and Schwartz, {Robert J.} and Hiroshi Okamoto and Takehiko Sasaki and Osamu Matsui and Masahide Asano and Adams, {Ralf H.} and Nobuyuki Takakura and Yoh Takuwa",
note = "Funding Information: We thank K. Mitsumori for comments on the histological study. We thank N. Mochizuki and K. Ando for assistance with the FRET imaging analysis. We thank N. Furusawa, K. Sunagawa and E. Kaneko for assistance with live-cell imaging using a Yokogawa confocal microscope system. We also thank Y. Ohta and T. Murakawa for technical assistance and T. Hirose for administrative assistance. C2α complementary DNA was obtained from J. Domin (Imperial College London). GFP-2 × FYVE and mRFP-2 × FYVE expression vectors were obtained from H. Stenmark (Oslo University Hospital) and Y. Ohsumi (Tokyo Institute of Technology), respectively. VE-cadherin-GFP expression vectors were obtained from N. Mochizuki (National Cerebral and Cardiovascular Center). The pRaichu-RhoA probe was obtained from M. Matsuda (Kyoto University). GFP-RhoAAsn19 and GFP-RhoAVal14 expression vectors were obtained from F. Valderrama (King{\textquoteright}s College London). This work was supported in part by grants-in-aid from the Japanese Ministry of Education, Culture, Sports, Science and Technology, the Japan Society for the Promotion of Science (to K. Yoshioka, N. Takuwa, Y.O. and Y.T.), the Honjin Foundation, the Mitsubishi Pharma Research Foundation and the SENSIN Medical Research Foundation (to K. Yoshioka).",
year = "2012",
month = oct,
doi = "10.1038/nm.2928",
language = "English",
volume = "18",
pages = "1560--1569",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "10",
}