Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin through nuclear factor-kappa B activation in endothelial cells

Vascular endothelial growth factor (VEGF) induces adhesion molecules on end othelial cells during inflammation. Here we examined the mechanisms underly ing VEGF-stimulated expression of intercellular adhesion molecule 1 (ICAM-1 ), vascular cell adhesion molecule 1 (VCAM-1)1 and E-selectin in human umbi lical vein endothelial cells. VEGF (20 ng/ml) increased expression of ICAM- 1, VCAM-1, and E-selectin mRNAs in a time-dependent manner. These effects w ere significantly suppressed by Flk-1/kinase-insert domain containing recep tor (KDR) antagonist and by inhibitors of phospholipase C, nuclear factor ( NF)-B-K, sphingosine kinase, and protein kinase C, but they were not affect ed by inhibitors of mitogen-activated protein/extracellular signal-regulate d kinase kinase (MEK) 1/2 or nitric-oxide synthase, Unexpectedly, the phosp hatidylinositol (PI) 3'-kinase inhibitor wortmannin enhanced both basal and VEGF-stimulated adhesion molecule expression, whereas insulin, a PI 3'-kin ase activator, suppressed both basal and VEGF-stimulated expression, Gel sh ift analysis revealed that VEGF stimulated NF-B-K activity, This effect was inhibited by phospholipase C, NF-B-K, or protein kinase C inhibitor, VEGF increased VCAM-1 and ICAM-1 protein levels and increased leukocyte adhesive ness in a NF-KB-dependent manner. These results suggest that VEGF-stimulate d expression of ICAM-1, VCARI-1, and E-selectin mRNAs was mainly through NF -KB activation with PI 3'-kinase-mediated suppression, but was independent of nitric oxide and MEK, Thus, VEGF simultaneously activates two signal tra nsduction pathways that have opposite functions in the induction of adhesio n molecule expression. The existence of parallel inverse signaling implies that the induction of adhesion molecule expression by VEGF is very finely r egulated.