Arteriogenesis Is Modulated on Bradykinin Receptor Signaling
Background: Positive outward remodeling of preexisting collateral arteries into functional conductance arteries, arteriogenesis, is a major endogenous rescue mechanism to prevent for cardiovascular ischemia. Collateral arterial growth is accompanied by kininogen expression in growing arteries, the precursor of kinins, which signal via the kinin receptors 1 (B1R) and kinin receptor 2 (B2R). The purpose of this study was to elucidate the functional role and mechanism of bradykinin receptor signaling in arteriogenesis.
Methods and Results: Bradykinin receptors positively affected arteriogenesis, with the contribution of B1R being more pronounced than B2R. In mice, arteriogenesis on femoral artery occlusion was significantly reduced in B1R mutant mice as evidenced by reduced microspheres and laser Doppler flow perfusion measurements. Transplantation of wild-type bone marrow cells into irradiated B1R mutant mice restored arteriogenesis, whereas bone marrow chimeric mice generated by reconstituting wild-type mice with B1R mutant bone marrow showed reduced arteriogenesis after femoral artery occlusion. In the rat brain 3-vessel occlusion arteriogenesis model, pharmacological treatment of B1R inhibited arteriogenesis and stimulation of B1R enhanced arteriogenesis. In the rat, femoral artery ligation combined with arterial venous shunt model resulted in flow-driven arteriogenesis, and treatment with B1R antagonist R715 decreased vascular remodeling and leukocyte invasion (monocytes) into the perivascular tissue. In monocyte migration assays, in vitro B1R agonists enhanced migration of monocytes.
Conclusions: Kinin receptors act as positive modulators of arteriogenesis in mice and rats. B1R can be blocked or therapeutically stimulated by B1R antagonists or agonists, respectively, involving a contribution of peripheral immune cells (monocytes) linking hemodynamic conditions with inflammatory pathways.
- Received January 17, 2011.
- Revision received June 16, 2011.
- Accepted June 20, 2011.
- © 2011 American Heart Association, Inc.