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 KV 1.3 potassium channels are expressed in vascular smooth muscle cells (VSMCs), where they contribute to proliferation rather than contraction and participate in vascular remodeling. KV 1.3 channels are also expressed in macrophages, where they assemble with KV 1.5 channels (KV 1.3/KV 1.5), whose activation generates a KV current. In macrophages, the KV 1.3/KV 1.5 ratio is increased by classical activation (M1). Whether these channels are involved in angiotensin II-induced vascular remodelling and whether they can modulate the macrophage phenotype in hypertension, remains unknown. We characterised the role of KV 1.3 channels in vascular damage in hypertension. Experimental approach We used angiotensin II (AngII)-infused mice treated with two selective KV 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 KV 1.3 channel expression in mice aorta and peritoneal macrophages which was abolished by HsTX[R14A] treatment. KV 1.3 inhibition did not prevent hypertension, vascular remodeling, 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. In peritoneal macrophages, AngII modified their electrophysiological properties indicating an M1-like activated state, characterised by enhanced expression of proinflammatory cytokines that induce endothelial dysfunction. These effects were prevented by KV 1.3 blockade. Conclusions and implications We unravelled a new role for KV 1.3 channels in the macrophage-dependent endothelial dysfunction induced by AngII in mice which might be due to the modulation of macrophage phenotype.