K(V)1.3 Channels Are Novel Determinants Of Macrophage-Dependent Endothelial Dysfunction In A Mouse Model With Angiotensin Ii-Induced Hypertension

Background and Purpose K(V)1.3 channels are expressed in vascular smooth muscle cells (VSMCs), where they contribute to proliferation rather than contraction and participate in vascular remodelling. K(V)1.3 channels are also expressed in macrophages, where they assemble with K(V)1.5 channels (K(V)1.3/K(V)1.5), whose activation generates a K-V current. In macrophages, the K(V)1.3/K(V)1.5 ratio is increased by classical activation (M1). Whether these channels are involved in angiotensin II (AngII)-induced vascular remodelling, and whether they can modulate the macrophage phenotype in hypertension, remains unknown. We characterized the role of K(V)1.3 channels in vascular damage in hypertension.Experimental Approach We used AngII-infused mice treated with two selective K(V)1.3 channel inhibitors (HsTX[R14A] and [EWSS]ShK). Vascular function and structure were measured using wire and pressure myography, respectively. VSMC and macrophage electrophysiology were studied using the patch-clamp technique; gene expression was analysed using RT-PCR.Key Results AngII increased K(V)1.3 channel expression in mice aorta and peritoneal macrophages which was abolished by HsTX[R14A] treatment. K(V)1.3 inhibition did not prevent hypertension, vascular remodelling, or stiffness but corrected AngII-induced macrophage infiltration and endothelial dysfunction in the small mesenteric arteries and/or aorta, via a mechanism independent of electrophysiological changes in VSMCs. AngII modified the electrophysiological properties of peritoneal macrophages, indicating an M1-like activated state, with enhanced expression of proinflammatory cytokines that induced endothelial dysfunction. These effects were prevented by K(V)1.3 blockade.Conclusions and Implications We unravelled a new role for K(V)1.3 channels in the macrophage-dependent endothelial dysfunction induced by AngII in mice which might be due to modulation of macrophage phenotype.