The bradykinin/B1 receptor promotes angiogenesis by up-regulation of endogenous FGF-2 in endothelium via the nitric oxide synthase pathway

Bradykinin (BK) mediates inflammation and contributes to angiogenesis. We assessed the mechanisms for BK contribution to angiogenesis. Nanomolar concentrations of BK induced angiogenesis in rabbit corneas in absence of inflammation. The effect was dose-dependent and mediated by the B1 receptor. 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 131 receptor agonist. In postcapillary venular endothelial cells (CVEC), B2 receptor activation induced inositol phosphate turnover and calcium transients, whereas the B1 receptor was coupled to nitric oxide synthase (NOS) up-regulation and activation and cGMP increase. Differential RT-PCR and Western blot analysis revealed FGF-2 up-regulation in cells exposed to BK or to the selective B1 agonist, whereas the B2 agonist was without effect. Consistently, BK and the B1 but not the B2 agonist exerted a proliferative effect on CVEC, which was prevented by anti-FGF-2 antibody and by NOS inhibition. These results demonstrate that BK is angiogenic despite its proinflammatory activity and that the B1 receptor is involved. The B 1 receptor is coupled to NOS activation and FGF-2 up-regulation, events not shared by the B2 receptor activation.