Abid Md Ruhul, Guo Shaodong, Minami Takashi, Spokes Katherine C, Ueki Kohjiro, Skurk Carsten, Walsh Kenneth, Aird William C
Department of Medicine, Beth Israel Deaconess Medical Center, RW-663, Boston, MA 02215, USA.
Arterioscler Thromb Vasc Biol. 2004 Feb;24(2):294-300. doi: 10.1161/01.ATV.0000110502.10593.06. Epub 2003 Dec 1.
Vascular endothelial growth factor (VEGF) is a potent angiogenic growth factor that promotes endothelial cell (EC) survival, migration, and permeability. The forkhead transcription factors FKHR, FKHRL1, and AFX are mammalian orthologues of DAF-16, a forkhead protein that controls longevity in Caenorhabditis elegans. In this study, we examined whether VEGF is coupled to phosphatidyl inositol 3-kinase (PI3K)/Akt/forkhead in ECs.
We demonstrate that human ECs express members of the forkhead family (FKHR, FKHRL1, and AFX) and that VEGF modulates the phosphorylation, subcellular localization, and transcriptional activity of one or more of these isoforms by a PI3K/Akt signaling pathway. VEGF inhibited EC apoptosis, promoted DNA synthesis and the G(1)-to-S transition, and reduced expression of the cyclin-dependent kinase inhibitor p27(kip1). Each of these effects was blocked by the PI3K inhibitor LY294002 or by a phosphorylation-resistant mutant of FKHRL1, but not by wild-type FKHRL1.
These results suggest that VEGF signaling in ECs is coupled to forkhead transcription factors through a PI3K/Akt-dependent pathway.
血管内皮生长因子（VEGF）是一种强大的血管生成生长因子，可促进内皮细胞（EC）的存活、迁移和通透性。叉头转录因子FKHR、FKHRL1和AFX是DAF-16的哺乳动物同源物，DAF-16是一种控制秀丽隐杆线虫寿命的叉头蛋白。在本研究中，我们检测了VEGF是否与EC中的磷脂酰肌醇3激酶（PI3K）/Akt/叉头相关联。
我们证明人EC表达叉头家族成员（FKHR、FKHRL1和AFX），并且VEGF通过PI3K/Akt信号通路调节这些异构体中一种或多种的磷酸化、亚细胞定位和转录活性。VEGF抑制EC凋亡，促进DNA合成和G(1)到S期转换，并降低细胞周期蛋白依赖性激酶抑制剂p27(kip1)的表达。这些效应中的每一种都被PI3K抑制剂LY294002或FKHRL1的磷酸化抗性突变体阻断，但未被野生型FKHRL1阻断。
这些结果表明，EC中的VEGF信号通过PI3K/Akt依赖性途径与叉头转录因子相关联。
