Regulation of mitogenesis by kinins in arterial smooth muscle cells

Am J Physiol. 1997 Jul;273(1 Pt 1):C7-20. doi: 10.1152/ajpcell.1997.273.1.C7.


Recent evidence suggests that bradykinin (BK) plays a role in regulating neointimal formation after vascular injury. The present study examined the mechanism whereby BK regulates platelet-derived growth factor (PDGF) AB-induced mitogenesis in smooth muscle cells from rat mesenteric artery. BK, but not other activators of phosphoinositidase C (e.g., angiotensin II), inhibited PDGF-stimulated mitogenesis. The B1 receptor agonist des-Arg9-BK (DABK) was more potent than the B2 agonist BK; smaller BK fragments had no activity. In studies in which the B2 receptor antagonist HOE-140 {D-Arg0[Hyp3,beta-(2-thienyl)-Ala5,D-Tic7,Oic 8]BK} and the B1 receptor antagonist DHOE [[D-Arg0,Hyp3,beta-(2-thienyl)-Ala5,D-Tic7,Oi c8,des-Arg9]BK] were used, both receptors independently mediated inhibition of PDGF-induced mitogenesis. There was no evidence for metabolism of BK to DABK. The rank potency for activating phosphoinositidase C and increasing intracellular Ca2+ (BK > DABK) was opposite that for inhibiting mitogenesis (DABK > BK). Inhibition of cyclooxygenase did not prevent the kinin-mediated inhibition. Kinetic analysis of the cell cycle effects of kinins on PDGF-stimulated mitogenesis revealed that continuous exposure to DABK or BK was inhibitory even when added shortly before the cells initiated DNA synthesis (S phase). However, short-term exposure (5-60 min) to DABK or BK was inhibitory only when added after exposure to PDGF. These data suggest that the B1 and B2 receptors potently inhibited PDGF-stimulated mitogenesis and proliferation by activating an alternative signal transduction cascade not involving phosphoinositidase C or prostaglandins. The inhibition occurred at a point late in progression of the cell cycle from G1 to S and was dependent on the presence of kinins after exposure to PDGF.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Bradykinin / analogs & derivatives*
  • Bradykinin / pharmacology*
  • Bradykinin Receptor Antagonists
  • Carotid Arteries / cytology
  • Carotid Arteries / drug effects
  • Carotid Arteries / physiology
  • Cell Division / drug effects
  • Cells, Cultured
  • Cyclooxygenase Inhibitors / pharmacology
  • Enzyme Activation
  • In Vitro Techniques
  • Mesenteric Arteries / cytology
  • Mesenteric Arteries / drug effects
  • Mesenteric Arteries / physiology
  • Mitosis / drug effects
  • Muscle Contraction / drug effects
  • Muscle, Smooth, Vascular / cytology*
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / physiology*
  • Phosphoric Diester Hydrolases / metabolism
  • Platelet-Derived Growth Factor / pharmacology*
  • Rats
  • Rats, Wistar
  • Receptor, Bradykinin B1
  • Receptor, Bradykinin B2
  • Receptors, Bradykinin / agonists


  • Bradykinin Receptor Antagonists
  • Cyclooxygenase Inhibitors
  • Platelet-Derived Growth Factor
  • Receptor, Bradykinin B1
  • Receptor, Bradykinin B2
  • Receptors, Bradykinin
  • bradykinin, des-Arg(9)-
  • icatibant
  • Phosphoric Diester Hydrolases
  • glycerophosphoinositol glycerophosphodiesterase
  • Bradykinin