Analysis of the biological function of vascular smooth muscle cells regulated by fibrinolytic factors

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Vascular smooth muscle cells (SMC) were successfully isolated from thoracic aorta of normal and fibrinolytic factor gene deficient mice. The wild-type SMC (WT/SMC) and the four SMC cultures, lacking urokinase-type plasminogen activator (u-PA^<-/->/SMC), tissue-type plasminogen activator (t-PA^<-/->/SMC), type 1 plasminogen activator inhibitor (PAI-1^<-/->/SMC), and u-PA receptor (u-PAR^<-/->/SMC) were employed to analyze their proliferative activities in the presence of mouse melanoma cells (B16). The growth rates of u-PA^<-/->/SMC, t-PA^<-/->/SMC, and PAI-1^<-/->/SMC as well as WT/SMC were not changed when they were co-cultured with B16 (mixed culture and two-chamber culture) in the presence of 10% fetal calf serum (FCS). On the other hand, the FCS-free conditioned medium of confluent B16 promoted the growth of these SMC to the same extent (〜200%) each of which was associated with both increased tyrosine phosphorylation of 77-kDa protein (7.5〜11-fold) and mitogen-activated protein kinase (MAPK) activity (2-fold). In contrast, only the growth of u-PAR^<-/->/SMC was arrested in these co-cultures. The B16 conditioned medium also suppressed the growth of the SMC of which the phosphorylation of 77- kDa protein and MAPK activity were not altered. These results indicate that these SMC were stimulated by B16-derived growth factor-like substance (s) and that the expressions of u-PA, t-PA and PAI-1 were not involved in these events. However, it is suggested that u-PAR plays an important role in the growth mechanism possibly by forming a functional unit with integrins. Thus, one of the biological responses of SMC to carcinoma cells may be the defense by increased growth of cell-mass against the metastatic process of carcinoma cells at the vascular wall.