Integrin regulation by vascular endothelial growth factor in human brain microvascular endothelial cells: role of alpha6beta1 integrin in angiogenesis.
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.
Lee
Tae-Hee
TH
Division of Experimental Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA.
Seng
Seyha
S
Li
Huchun
H
Kennel
Stephen J
SJ
Avraham
Hava Karsenty
HK
Avraham
Shalom
S
D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000166:cytology / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D006801:Humans; D039121:Integrin alpha6beta1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018919:Neovascularization, Physiologic; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000096:biosynthesis; D040262:Receptors, Vascular Endothelial Growth Factor / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
D039121:Integrin alpha6beta1; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor