UROKINASE AND TISSUE-TYPE PLASMINOGEN-ACTIVATOR ARE REQUIRED FOR THE MITOGENIC AND CHEMOTACTIC EFFECTS OF BOVINE FIBROBLAST GROWTH-FACTOR AND PLATELET-DERIVED GROWTH FACTOR-BB FOR VASCULAR SMOOTH-MUSCLE CELLS

The present study was undertaken to evaluate in vitro the relative imp ortance of tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) in the mitogenic and chemotactic potenti al of bovine fibroblast growth factor (bFGF) and platelet-derived grow th factor (PDGF)-BB for smooth muscle cells (SMC), Aortic SMC were iso lated from transgenic mice showing single inactivations of the t-PA, u -PA, plasminogen activator inhibitor-1, or urokinase-type plasminogen activator receptor (u-PAR) genes. With regard to serum-induced prolife ration, all cell types showed similar responses, However, SMC isolated from t-PA-deficient mice did not proliferate or migrate in response t o PDGF, whereas SMC isolated from u-PA-deficient animals appeared to b e much less sensitive to bFGF than the cells isolated from the other a nimals, Supplementation of cells from deficient animals with exogenous murine t-PA or u-PA restored the normal response of the growth factor s with regard to both migration and proliferation, The mitogenic and c hemotactic responses of bFGF were specifically inhibited in u-PAR-defi cient cells or in wild-type SMC, cultured in the presence of antibodie s to u-PAR, The role of u-PA and t-PA in bFGF and PDGF-induced growth and migration of SMC was not dependent on plasmin generation and activ ity as demonstrated by the inactivity of epsilon-aminocaproic acid and aprotinin, A 4-5-fold increase in the steady-state levels of u-PA and t-PA mRNA and proteins were observed after 24 h of incubation of the cell cultures with bFGF and PDGF-BB, respectively, These results there fore indicate that, at least in vitro, t-PA is an important element of the activity of PDGF-BB with regard to the proliferation and migratio n of SMC whereas u-PA is a key factor in the effect of bFGF on SMC.