Decreased flow-dependent dilation in carotid arteries of tissue kallikrein-knockout mice

Flow-dependent dilation is a fundamental mechanism by which large arteries ensure appropriate blood supply to tissues. We investigated whether or not the vascular kallikrein-kinin system, especially tissue kallikrein (TK), contributes to flow-dependent dilation by comparing wild-type and TK-knockout mice in which the presence or absence of TK expression was verified. We examined in vitro changes in the outer diameter of perfused carotid arteries from TK+/+ and TK-/- mice. In both groups, exogenous bradykinin caused a similar dilation that was abolished by the B-2 receptor antagonist HOE-140, as well as by the NO synthase inhibitor N-omega-nitro-L-arginine methyl ester. However, purified kininogen dilated only TK+/+ arteries, demonstrating the essential role of TK in the vascular formation of kinins, In TK+/+ arteries, increasing intraluminal flow caused a larger endothelium-dependent dilation than that seen in TK-/-. both strains the flow response was mediated by NO and by endothelium-derived hyperpolarizing factor, whereas in TK-/- vasoconstrictor prostanoids participated as well. HOE-140 impaired flow-dependent dilation in TK+/+ arteries while showing no effect in TK-/-. This compound reduced the flow response in TK+/+ arteries to a level similar to that in TK-/-. After NO synthase inhibition, HOE-140 no longer affected the response of TK+/+. Impaired flow-dependent dilation was also observed in arteries from knockout mice lacking bradykinin B-2 receptors as compared with wild-type animals. This study demonstrates the active contribution of the vascular kallikrein-kinin system to one-third of the flow-dependent dilation response via activation of B-2 receptors coupled to endothelial NO release.