Autocrine control of angiogenesis induced by bradykinin/B1 receptor: role of endothelial nitric oxide synthase and fibroblast growth factor-2

Bradykinin (BK) is a potent mediator of permeability and inflammation which has been reported to contribute to angiogenesis. We assesed whether BK contribution toangiogenesis could occur despite its role in inflammation. Nanomolar concentration of BK induced angiogenesis in the rabbit comea in the absence of an inflammatory component. The effect was dose-dependent and mediated by the B1 receptor. Conversely, B2 receptor stimulation failed to directly promote vascular growth unless inflammation was induced. Anti-fibroblast growth factor-2 (FGF-2) antibody blocked the effect of BK or B1 receptor agonist, suggesting the existence of an endogenous control of angiogenesis. In postcapillary endothelial cells isolated from bovine coronary venules (CVEC) nitric oxide synthase (NOS) upregulation and activationoccurred in response to B1 receptor stimulation, while B2 receptor activation failed to stimulate NOS pathway. Moreover, BK and the B1 but not the B2 agonist exerted a proliferative effect on CVEC which was prevented by anti-FGF-2 antibodies and by NOS inhibition. These results demonstrate that BK is angiogenic despite its pro-inflammatory activity and that the B1 receptor is involved. Moreover the B1 receptor is coupled to NOS activation and endogenous FGF-2 upregulation, events not shared by the B2 receptor activation.