Angiogenesis activators and inhibitors differentially regulate caveolin-1 expression and caveolae formation in vascular endothelial cells - Angiogenesis inhibitors block vascular endothelial growth factor-induced down-regulation of caveolin-1
Angiogenesis activators and inhibitors differentially regulate caveolin-1 expression and caveolae formation in vascular endothelial cells - Angiogenesis inhibitors block vascular endothelial growth factor-induced down-regulation of caveolin-1
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DOI：
10.1074/jbc.274.22.15781
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发表时间：
1999-05-28
影响因子：
4.8
通讯作者：
Lisanti, MP
中科院分区：
文献类型：
--
作者：
Liu, J;Razani, B;Lisanti, MP
血管生成是通过血管内皮细胞增殖形成新血管的过程。最近发现了多种血管生成抑制剂，可拮抗血管内皮生长因子（VEGF）和碱性成纤维细胞生长因子（bFGF）的作用。然而，这些不同的血管生成抑制剂发挥其共同作用的机制在很大程度上仍然未知。已知在体外和体内血管内皮细胞中高表达的Caveolin-1和-2，在这里，我们研究了caveolin在血管生成反应中的潜在作用，为此，我们使用了建立良好的人脐静脉内皮细胞系ECV 304，用已知的血管生成生长因子（VEGF， bFGF或肝细胞生长因子/分散因子）处理ECV 304细胞，导致Caveolin-1的表达显著降低。这种下调事件对caveolin-1是选择性的，因为在这些生长因子刺激的条件下，caveolin-2水平保持不变。在透射电镜下，vegf诱导的caveolin-1表达下调也导致了细胞表面小窝细胞器的形态学损失，多种血管生成抑制剂（包括血管抑制素、富马西林、2-甲氧基雌二醇、转化生长因子-A和沙利度胺）在免疫印迹和免疫荧光显微镜下有效地阻断了vegf诱导的caveolin-1的下调。单独使用血管生成抑制剂治疗对caveolin-1的表达没有显著影响。PD98059是一种丝裂原活化蛋白激酶的特异性抑制剂，也是一种已知的血管生成抑制剂，它也阻断了vegf诱导的caveolin-1的下调。此外，我们发现caveolin-1在体内可以作为VEGF-R （KDR）信号转导的负调节因子，因此，下调caveolin-1可能是内皮细胞增殖途径的重要一步。
Angiogenesis is the process by which new blood vessels are formed via proliferation of vascular endothelial cells. A variety of angiogenesis inhibitors that antagonize the effects of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have recently been identified. However, the mechanism by which these diverse angiogenesis inhibitors exert their common effects remains largely unknown. Caveolin-1 and -2 are known to be highly expressed in vascular endothelial cells both in vitro and in vivo, Here, we examine the potential role of caveolins in the angiogenic response, For this purpose, we used the well established human umbilical vein endothelial cell line, ECV 304, Treatment of ECV 304 cells with known angiogenic growth factors (VEGF, bFGF, or hepatocyte growth factor/scatter factor), resulted in a dramatic reduction in the expression of caveolin-1, This down-regulation event was selective for caveolin-1, as caveolin-2 levels remained constant under these conditions of growth factor stimulation. VEGF-induced down-regulation of caveolin-1 expression also resulted in the morphological loss of cell surface caveolae organelles as seen by trans mission electron microscopy, A variety of well characterized angiogenesis inhibitors (including angiostatin, fumagillin, 2-methoxy estradiol, transforming growth factor-A and thalidomide) effectively blocked VEGF-induced down-regulation of caveolin-1 as seen by immunoblotting and immunofluorescence microscopy, However, treatment with angiogenesis inhibitors alone did not significantly affect the expression of caveolin-1. PD98059, a specific inhibitor of mitogen-activated protein kinase and a known angiogenesis inhibitor, also blocked the observed VEGF-induced down-regulation of caveolin-1. Furthermore, we show that caveoliln-1 can function as a negative regulator of VEGF-R (KDR) signal transduction in vivo, Thus, down-regulation of caveolin-1 may be an important step along the pathway toward endothelial cell proliferation.