MITOGEN-ACTIVATED PROTEIN-KINASE AND PROLIFERATION OF HUMAN VASCULAR SMOOTH-MUSCLE CELLS

The intracellular messenger mitogen-activated protein kinase (MAPK) is activated in vascular smooth muscle cells (SMC) by various growth fac tors as well as by agonists that have no proliferative effect. We expl ored the hypotheses that SMC proliferation is associated with a specif ic pattern of MAPK activation by evaluating the kinetics of MAPK activ ation and tyrosine phosphorylation and the intracellular location of M APK in SMC following addition of agonists of varying mitogenic potenti al. A peak in MAPK activation and tyrosine phosphorylation occurred 3- 10 min after the addition of agonists to SMC derived from human saphen ous vein (early phase), followed by a plateau of activity, which was v ariable in duration (late phase). A correlation was not found between mitogenicity and the degree to which MAPK became activated or tyrosine phosphorylated in the early phase. However, the duration of MAPK acti vation and tyrosine phosphorylation correlated strongly with the abili ty of agonists to stimulate SMC proliferation. Nuclear translocation o f MAPK was associated with SMC proliferation, although the degree to w hich each agonist induced nuclear translocation did not parallel its m itogenic potential. The relative dependency of all three events on pro tein kinase C differed for each agonist and was greater in the late ve rsus the early phase. Thus, in human SMC, nuclear translocation of MAP K and prolonged activation and tyrosine phosphorylation of MAPK are as sociated with growth factor-induced mitogenesis.