REGULATION OF MITOGENESIS BY KININS IN ARTERIAL SMOOTH-MUSCLE CELLS

Recent evidence suggests that bradykinin (BK) plays a role in regulati ng neointimal formation after vascular injury. The present study exami ned the mechanism whereby BK regulates platelet-derived growth factor (PDGF) AB-induced mitogenesis in smooth muscle cells from rat mesenter ic artery. BK, but not other activators of phosphoinositidase C (e.g., angiotensin II), inhibited PDGF-stimulated mitogenesis. The B-1 recep tor agonist des-Arg(9)-BK (DABK) was more potent than the Bz agonist B K; smaller BK fragments had no activity. In studies in which the Bz re ceptor antagonist HOE-140 (D-Arg(0)[Hyp(3), beta-(2-thienyl)-Ala(5),D- Tic(7),Oic(8)]BC) and the B-1 receptor antagonist DHOE a-(2-thienyl)Al a(5),D-Tic(7),Oic(8),des-Arg(9)]BK] were used, both receptors independ ently mediated inhibition of PDGF-induced mitogenesis. There was no ev idence for metabolism of BK to DABK. The rank potency for activating p hosphoinositidase C and increasing intracellular Ca2+ (BK > DABK) was opposite that for inhibiting mitogenesis (DABK > BK). Inhibition of cy clooxygenase did not prevent the kinin-mediated inhibition. Kinetic an alysis of the cell cycle effects of kinins on PDGF-stimulated mitogene sis revealed that continuous exposure to DABK or BK was inhibitory eve n when added shortly before the cells initiated DNA synthesis (S phase ). However, short-term exposure (5-60 min) to DABK or BK was inhibitor y only when added after exposure to PDGF. These data suggest that the B-1 and B-2 receptors potently inhibited PDGF-stimulated mitogenesis a nd proliferation by activating an alternative signal transduction casc ade not involving phosphoinositidase C or prostaglandins. The inhibiti on occurred at a point late in progression of the cell cycle from G(1) to S and was dependent on the presence of kinins after exposure to PD GF.