Regulation of Integrin Expression and Activation by VEGF in Human Brain Microvascular Endothelial Cells: Implication of α₆ Integrin in Angiogenesis.

The precise role of vascular endothelial growth factor (VEGF) in the regulation of integrins is not well elucidated due to their high redundancy. Here, we examined the effects of VEGF on the expression and activation of integrins in human brain microvascular endothelial cells (HBMECs). Using human cDNA arrays and Ribonuclease (RNase) protection assays which cover most of the known integrins, we observed that VEGF significantly upregulated the mRNA expression of α₁, α₂, and α₆ integrins in HBMECs. While VEGF was reported to induce α₁ and α₂ integrins, the observation of α₆ integrin induction by VEGF is novel. Using small interfering RNA (siRNA) oligonucleotides for α₆ integrin, we observed downregulation of the cell surface expression of α₆ integrin in HBMECs. This downregulation resulted in inhibition of both HBMEC capillary morphogenesis and of the VEGF-induced adhesion and migration of the cells. VEGF also induced the activation of α₆ integrin in the HBMECs. Functional blocking of α₆ integrin by its specific antibody led to inhibition of VEGF-induced adhesion and migration as well as of in vivo angiogenesis, and significantly suppressed tumor angiogenesis and breast carcinoma cell growth in vivo. These results indicate that VEGF can modulate the in vitro angiogenesis of HBMECs via increased expression and activation of the α₆ integrin, and that this integrin participates in VEGF-driven angiogenesis in vivo.