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

Kazuaki Yoshioka, Kotaro Yoshida, Hong Cui, Tomohiko Wakayama, Noriko Takuwa, Yasuo Okamoto, Wa Du, Xun Qi, Ken Asanuma, Kazushi Sugihara, Sho Aki, Hidekazu Miyazawa, Kuntal Biswas, Chisa Nagakura, Masaya Ueno, Shoichi Iseki, Robert J. Schwartz, Hiroshi Okamoto, Takehiko Sasaki, Osamu MatsuiMasahide Asano, Ralf H. Adams, Nobuyuki Takakura, Yoh Takuwa

Research output: Contribution to journalArticlepeer-review

122 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1560-1569
Number of pages10
JournalNature Medicine
Volume18
Issue number10
DOIs
Publication statusPublished - 2012 Oct

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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