Decreased Flow-Dependent Dilation in Carotid Arteries of Tissue Kallikrein–Knockout Mice

Sonia Bergaya, Pierre Meneton, May Bloch-Faure, Eric Mathieu, François Alhenc-Gelas, Bernard I. Lévy, Chantal M. Boulanger
2001 Circulation Research  
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 ϩ/ϩ and TK Ϫ/Ϫ mice. In both groups,
more » ... nous 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 -nitro-L-arginine methyl ester. However, purified kininogen dilated only TK ϩ/ϩ arteries, demonstrating the essential role of TK in the vascular formation of kinins. In TK ϩ/ϩ arteries, increasing intraluminal flow caused a larger endothelium-dependent dilation than that seen in TK Ϫ/Ϫ . In both strains the flow response was mediated by NO and by endothelium-derived hyperpolarizing factor, whereas in TK Ϫ/Ϫ vasoconstrictor prostanoids participated as well. HOE-140 impaired flow-dependent dilation in TK ϩ/ϩ arteries while showing no effect in TK Ϫ/Ϫ . This compound reduced the flow response in TK ϩ/ϩ arteries to a level similar to that in TK Ϫ/Ϫ . After NO synthase inhibition, HOE-140 no longer affected the response of TK ϩ/ϩ . 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. (Circ Res. 2001;88: 593-599.) Key Words: bradykinin Ⅲ kininogen Ⅲ flow-dependent vasodilation Ⅲ endothelium Ⅲ bradykinin B
doi:10.1161/01.res.88.6.593 pmid:11282893 fatcat:i7xcbzvkovhl7mtt5u532eii6q