B1 receptor involvement in the effect of bradykinin on venular endothelial cell proliferation and potentiation of FGF‐2 effects

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Abstract
Bradykinin (BK) contributes to the inflammatory response inducing vasodilation of postcapillary venules and has been demonstrated to induce neovascular growth in subcutaneous rat sponges. In this study the ability of BK to stimulate cell growth and migration in cultured endothelium from coronary postcapillary venules (CVEC) has been investigated. [3H]‐thymidine incorporation in subconfluent and synchronised CVEC was used to monitor DNA synthesis over 24 h. BK promoted a concentration‐dependent increase of DNA synthesis with maximal activity at 100 nm. At this concentration BK also induced 18 fold accumulation of c‐Fos protein immunoreactivity in the nucleus within 1 h from peptide exposure. The total number of cells recovered after 48 h exposure to BK was increased in a concentration‐dependent manner. Maximal effect was produced by 100 nm concentration of the peptide which produced 50% increase in cell number. The selective B1 receptor agonist Des‐Arg9‐BK mimicked the proliferative effect of BK, while the B2 receptor agonist kallidin was devoid of any activity. The proliferation induced by BK was abolished in a concentration‐dependent manner by the addition of the B1 selective antagonist Des‐Arg9‐Leu8‐BK, while the selective B2 receptor antagonist HOE140 did not modify BK‐induced growth. DNA synthesis and growth promoted by a threshold concentration of fibroblast growth factor‐2 (FGF‐2) (0.25 nm) were potentiated by increasing concentrations of BK and Des‐Arg9‐BK. Endothelial cell migration assessed by the Boyden Chamber procedure was not promoted by BK or the selective B1 and B2 receptor agonists. These data are the first demonstration that BK promotes growth of endothelial cells from postcapillary venules. The mitogenic activity of BK involves c‐Fos expression and potentiates the growth promoting effect of FGF‐2. Only the B1 receptor appears to be responsible for the proliferation induced by BK and suggests that this type of receptor might be implicated in favouring angiogenesis of coronary venules. British Journal of Pharmacology (1998) 124, 1286–1292; doi:10.1038/sj.bjp.0701943