K 1.3 channels are novel determinants of macrophage-dependent endothelial dysfunction in angiotensin II-induced hypertension in mice.

Background And Purpose: K 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 1.3 channels are also expressed in macrophages, where they assemble with K 1.5 channels (K 1.3/K 1.5), whose activation generates a K current. In macrophages, the K 1.3/K 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 1.3 channels in vascular damage in hypertension.

Experimental Approach: We used AngII-infused mice treated with two selective K 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 1.3 channel expression in mice aorta and peritoneal macrophages which was abolished by HsTX[R14A] treatment. K 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 1.3 blockade.

Conclusions And Implications: We unravelled a new role for K 1.3 channels in the macrophage-dependent endothelial dysfunction induced by AngII in mice which might be due to modulation of macrophage phenotype.