Rho family GTPases regulate VEGF-stimulated endothelial cell motility

Migration of endothelial cells induced by vascular endothelial growth facto r (VEGF) is a critical step in angiogenesis. Stimulation of motility by gro wth factors such as VEGF requires interaction with the signal transduction pathways activated by the extracellular matrix (ECM). Here we demonstrate t hat the Rac GTPase is the critical intersection activated by type 1 collage n ECM and VEGF during stimulation of endothelial cell motility. To analyze the role of the Rho family GTPases in VEGF-stimulated endothelial cell chem otaxis and ECM-stimulated haptotaxis, we transduced the respective fusion p roteins in human foreskin dermal endothelial cells using a Tat peptide from the human immunodeficiency virus Tat protein. VEGF signaling required Rac activation during chemotaxis, and Rac and Cdc42 were activated during hapto taxis on type I collagen. Similar to VEGF, Rac activation induced an increa se in endothelial cell stress fiber and focal adhesion. Surprisingly, Rho a ctivation was not present in collagen-induced haptotaxis or stimulation of chemotaxis by VEGF, although Rho induced stress fibers and focal adhesions similar to Rac activation. The result of constitutive Rho activation was an inhibition of haptotaxis. Thus, Rac is required and sufficient for the act ivation of endothelial cell haptotaxis and VEGF-stimulated chemotaxis. (C) 2001 Academic Press.