Lee Tae-Hee, Seng Seyha, Li Huchun, Kennel Stephen J, Avraham Hava Karsenty, Avraham Shalom
Division of Experimental Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA.
J Biol Chem. 2006 Dec 29;281(52):40450-60. doi: 10.1074/jbc.M607525200. Epub 2006 Nov 2.
The precise role of vascular endothelial growth factor (VEGF) in regulating integrins in brain microvascular endothelial cells is unknown. Here, we analyzed VEGF effects on integrin expression and activation in human brain microvascular endothelial cells (HBMECs). Using human cDNA arrays and ribonuclease (RNase) protection assays, we observed that VEGF up-regulated the mRNA expression of alpha(6) integrin in HBMECs. VEGF significantly increased alpha(6)beta(1) integrin expression, but not alpha(6)beta(4) integrin expression in these cells. Specific down-regulation of alpha(6) integrin expression by small interfering RNA (siRNA) oligonucleotides inhibited both the capillary morphogenesis of HBMECs and their adhesion and migration. Additionally, VEGF treatment resulted in activation of alpha(6)beta(1) integrins in HBMECs. Functional blocking of alpha(6) integrin with its specific antibody inhibited the VEGF-induced adhesion and migration as well as in vivo angiogenesis, and markedly suppressed tumor angiogenesis and breast carcinoma growth in vivo. Thus, VEGF can modulate angiogenesis via increased expression and activation of alpha(6)beta(1) integrins, which may promote VEGF-driven tumor angiogenesis in vivo.
血管内皮生长因子（VEGF）在调节脑微血管内皮细胞整合素中的精确作用尚不清楚。在此，我们分析了VEGF对人脑微血管内皮细胞（HBMECs）整合素表达和激活的影响。使用人类cDNA阵列和核糖核酸酶（RNase）保护分析，我们观察到VEGF上调了HBMECs中α(6)整合素的mRNA表达。VEGF显著增加了这些细胞中α(6)β(1)整合素的表达，但未增加α(6)β(4)整合素的表达。通过小干扰RNA（siRNA）寡核苷酸特异性下调α(6)整合素表达，抑制了HBMECs的毛细血管形态发生及其黏附与迁移。此外，VEGF处理导致HBMECs中α(6)β(1)整合素的激活。用其特异性抗体对α(6)整合素进行功能阻断，抑制了VEGF诱导的黏附与迁移以及体内血管生成，并显著抑制了体内肿瘤血管生成和乳腺癌生长。因此，VEGF可通过增加α(6)β(1)整合素的表达和激活来调节血管生成，这可能在体内促进VEGF驱动的肿瘤血管生成。
