Bradykinin B 1 Receptor Mediates Inhibition of Neointima Formation in Rat Artery After Balloon Angioplasty

Abstract

Abstract —We evaluated the effects of the kallikrein-kinin system on the proliferation and migration of primary cultured vascular smooth muscle cells (VSMCs) in vitro and neointima formation in balloon-injured rat carotid arteries in vivo. In cultured rat VSMCs, tissue kallikrein inhibited cell proliferation, and this inhibitory effect was blocked by Sar-Tyr-Aca(ε)-Lys [ d -βNal 7 ,Ile 8 ]-des-Arg 9 -bradykinin, a bradykinin B 1 receptor antagonist, and by icatibant, a bradykinin B 2 receptor antagonist. Platelet-derived growth factor significantly increased the expression of the B 1 receptor but not the B 2 receptor in VSMCs. Platelet-derived growth factor–induced cell migration was significantly attenuated by des-Arg 9 -bradykinin and to a lesser degree by bradykinin. Endogenous B 1 receptor mRNA increased in rat carotid arteries after balloon angioplasty. After local delivery of adenovirus carrying the human tissue kallikrein gene into the rat carotid artery, we observed a 54% reduction in the intima/media ratio at the injured site compared with the control ratio (n=7, P <0.01). Administration of the B 1 receptor antagonist via minipumps blocked the protective effect of kallikrein and partially reversed the intima/media ratio toward the control ratio. Kallikrein gene delivery results in the regeneration of endothelium compared with the control groups, and the B 1 receptor antagonist abolished this effect. Nitrite/nitrate, cGMP, and cAMP levels in balloon-injured arteries significantly increased after kallikrein gene delivery, whereas the B 1 receptor antagonist abolished these increases (n=4 or 5, P <0.05). These results indicate that the B 1 receptor contributes to the reduction of neointima formation via the promotion of reendothelialization and inhibition of VSMC proliferation and migration through NO-cGMP and cAMP signaling pathways. This study provides significant implications in treating restenosis after revascularization.