Department of Physiology, Kanazawa University School of Medicine, Kanazawa, Japan.
Nat Med. 2012 Oct;18(10):1560-9. doi: 10.1038/nm.2928. Epub 2012 Sep 16.
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.
磷脂酰肌醇 3-激酶（PI3K）的 II 类 α-同工型（PI3K-C2α）位于内体、反式高尔基体网络和网格蛋白包被小泡中；然而，其功能作用尚不清楚。PI3K-C2α 的全局或内皮细胞特异性缺失导致胚胎致死，原因是发芽血管生成和血管成熟缺陷。内皮细胞中 PI3K-C2α 的敲低导致富含 PI3-磷酸的内体数量减少，内体运输受损，VE-钙粘蛋白向内皮细胞连接处的传递受损，连接组装缺陷。PI3K-C2α 的敲低还损害了内皮细胞信号转导，包括血管内皮生长因子受体内化和内体 RhoA 的激活。PI3K-C2α 敲低的综合影响导致内皮细胞迁移、增殖、管状形成和屏障完整性受损。体内内皮 PI3K-C2α 缺乏抑制缺血后和肿瘤血管生成，并降低血管屏障功能，对过敏反应的敏感性大大增加，对血管紧张素 II 输注的反应性增加，更容易形成夹层主动脉瘤。因此，PI3K-C2α 在血管形成和屏障完整性中具有关键作用，是血管疾病的新治疗靶点。
