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Mechanisms of MAPK activation by bradykinin in vascular smooth muscle cells

V Velarde1, M E Ullian, T A Morinelli

  • 1Department of Medicine, Medical University of South Carolina and Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, South Carolina 29425, USA.

The American Journal of Physiology
|August 13, 1999
PubMed

Insights

Bradykinin (BK) activates the B(2)-kinin receptor in vascular smooth muscle cells (VSMC), triggering a signaling cascade that leads to mitogen-activated protein kinase (MAPK) activation and potentially contributing to VSMC proliferation in vascular injury.

Area of Science:

  • Vascular biology
  • Cell signaling
  • Biochemistry

Background:

  • Vascular smooth muscle cell (VSMC) proliferation is key in atherosclerosis after endothelial injury.
  • The role of the vascular kallikrein-kinin system in vascular disease remains unclear.

Purpose of the Study:

  • To characterize the signal transduction pathway for mitogen-activated protein kinase (MAPK) activation by bradykinin (BK) in VSMCs.
  • To investigate the contribution of the B(2)-kinin receptor to BK-induced signaling in VSMCs.

Main Methods:

  • VSMCs were treated with BK (10(-10)-10(-7) M) and analyzed for protein tyrosine phosphorylation.
  • B(2)- and B(1)-kinin receptor antagonists were used to assess receptor involvement.
  • Immunoprecipitation and immunoblotting were employed to detect focal adhesion kinase (p125(FAK)) and p60(src) association with growth factor receptor binding protein-2.
  • MAPK activity was measured, and the effects of pertussis toxin, cholera toxin, protein kinase C inhibitors, and MAPK kinase inhibitors were evaluated.

Main Results:

  • BK rapidly and dose-dependently increased tyrosine phosphorylation of several proteins in VSMCs.
  • The B(2)-kinin receptor antagonist HOE-140 blocked BK's effects, while the B(1) antagonist did not.
  • BK induced tyrosine phosphorylation of p125(FAK) and promoted p60(src) association with growth factor receptor binding protein-2.
  • BK significantly increased MAPK activity, an effect inhibited by protein kinase C and MAPK kinase inhibitors.

Conclusions:

  • Activation of the B(2)-kinin receptor by BK in VSMCs initiates multiple second messengers converging on MAPK activation.
  • This BK-induced MAPK activation pathway provides a basis for studying BK's role in VSMC proliferation during vascular injury.

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