PTEN modulates vascular endothelial growth factor-mediated signaling and angiogenic effects
PTEN modulates vascular endothelial growth factor-mediated signaling and angiogenic effects
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DOI：
10.1074/jbc.m110219200
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发表时间：
2002-03-29
影响因子：
4.8
通讯作者：
Kontos, CD
中科院分区：
文献类型：
--
作者：
Huang, JH;Kontos, CD
磷脂酰肌醇3-激酶是由血管内皮生长因子(VEGF)激活的，而许多血管生成的细胞反应是由磷脂酰肌醇3-激酶的脂类产物调节的。肿瘤抑制基因PTEN可下调磷脂酰肌醇3-激酶信号转导，但PTEN对血管内皮生长因子介导的信号转导和血管生成的影响尚不清楚。腺病毒介导的显性负性PTEN突变体(PTEN-C/S)过表达抑制培养的内皮细胞内源性PTEN可增强血管内皮生长因子介导的Akt磷酸化，这种作用与肿瘤坏死因子-α诱导细胞凋亡后caspase-3裂解、caspase-3活性降低和DNA降解有关。PTEN-C/S的过表达也促进了血管内皮细胞的增殖和迁移。相反，野生型PTEN的过表达抑制了血管内皮生长因子的抗凋亡、增殖和趋化作用。此外，PTEN-C/S在大鼠主动脉环实验中增加了血管萌发的长度，并在体外血管生成实验中调节了血管内皮生长因子介导的血管形成，而PTEN-野生型则抑制了这些作用。综上所述，这些发现表明PTEN有效地调节了血管内皮生长因子介导的信号和功能，并且PTEN在促进或抑制血管生成的治疗方法中是一个可行的靶点。
Phosphatidylinositol 3-kinase is activated by vascular endothelial growth factor (VEGF), and many of the angiogenic cellular responses of VEGF are regulated by the lipid products of phosphatidylinositol 3-kinase. The tumor suppressor PTEN has been shown to down-regulate phosphatidylinositol 3-kinase signaling, yet the effects of PTEN on VEGF-mediated signaling and angiogenesis are unknown. Inhibition of endogenous PTEN in cultured endothelial cells by adenovirus-mediated overexpression of a dominant negative PTEN mutant (PTEN-C/S) enhanced VEGF-mediated Akt phosphorylation, and this effect correlated with decreases in caspase-3 cleavage, caspase-3 activity, and DNA degradation after induction of apoptosis with tumor necrosis factor-alpha. Overexpression of PTEN-C/S also enhanced VEGF-mediated endothelial cell proliferation and migration. In contrast, overexpression of wild-type PTEN inhibited the anti-apoptotic, proliferative, and chemotactic effects of VEGF. Moreover, PTEN-C/S increased the length of vascular sprouts in the rat aortic ring assay and modulated VEGF-mediated tube formation in an in vitro angiogenesis assay, whereas PTEN-wild type inhibited these effects. Taken together, these findings demonstrate that PTEN potently modulates VEGF-mediated signaling and function and that PTEN is a viable target in therapeutic approaches to promote or inhibit angiogenesis.