TYROSINE KINASE INHIBITION PREVENTS DEFORMATION-STIMULATED VASCULAR SMOOTH-MUSCLE GROWTH

The goal of this study was to determine the role of tyrosine phosphory lation in transducing deformation-stimulated vascular smooth muscle gr owth. Rat aorta-derived vascular smooth muscle cells were cultured on flexible silicone elastomer membranes and subjected to cyclic deformat ion (15 cycles per minute, deformed 2 seconds, relaxed 2 seconds), Def ormation significantly increased proto-oncogene expression, [H-3]thymi dine incorporation, [H-3]leucine incorporation, and cell number. Time course studies showed an 8-hour lag between initiation of cell deforma tion acid onset of [H-3]thymidine incorporation, with peak levels achi eved after 18 to 24 hours. Western analysis of protein blots from defo rmed cells (10 minutes) demonstrated increased levels of phosphotyrosi ne-containing proteins having molecular weights of 110 to 130 and 70 t o 80 kD. Deformation-stimulated tyrosine phosphorylation was prevented by the tyrosine kinase inhibitor Herbimycin A. Tyrosine kinase inhibi tion also prevented deformation-stimulated vascular smooth muscle cell growth as measured by [H-3]thymidine incorporation. Cyclic deformatio n stimulates vascular smooth muscle proliferation through activation o f tyrosine kinases. Inhibition of tyrosine phosphorylation is an effec tive means of preventing deformation-induced vascular smooth muscle gr owth in vitro.