THE REGULATION OF ENDOTHELIAL-CELL MOTILITY BY P21 RAS

Directed endothelial cell (EC) movement is required for the developmen t and repair of blood vessels and plays a critical role in angiogenic processes obligatory for large tumor formation. We now report that vas proteins have a critical role in regulation of movement of normal mam malian cells. Bovine aortic EC microinjected with oncogenic Ha-ras ent er further into an artificial wound than uninjected cells. Treatment w ith oncogenic Ha-ras also converts the cell paths from nearly linear i n control cells to apparent 'random-walk' trajectories in treated cell s, suggesting that oncogenic vas alters the normal control processes r egulating cell motility. Botulinum toxin C blocks uas-stimulated motil ity indicating that a member of the p21 rho family is a downstream par ticipant in the motile pathway. In related experiments we have observe d that microinjection of the neutralizing, Pas-specific, Y13-259 monoc lonal antibody completely blocks both basal and basic fibroblast growt h factor-stimulated movement of aortic EC. Y13-259 blocks the initiati on of EC movement, as well as the continued progress of cells already in motion, suggesting that uas activity is continuously required throu ghout the motile process. Together these data indicate that ras is an integral component of the signaling pathway regulating cell movement.