Inwardly-rectifying K + channels are major contributors to flow-induced vasodilation in resistance arteries

Aims: Inwardly rectifying K+ (Kir) channels are known to be sensitive to flow, but their role in flow-induced endothelial responses is not known. The goal of this study is to establish the role of Kir channels in flow-induced vasodilation and to provide first insights into the mechanisms responsible for Kir signaling in this process. Methods and Results: First, we establish that primary endothelial cells isolated from murine mesenteric arteries express functional Kir2.1 channels sensitive to shear stress. Then, using the Kir2.1+/- heterozygous mouse model, we establish that downregulation of Kir2.1 results in significant decrease in shear-activated Kir currents and inhibition of endothelium-dependent flow-induced vasodilation (FIV) assayed in pressurized mesenteric arteries pre-constricted with endothelin-1. Deficiency in Kir2.1 also results in the loss of flow-induced phosphorylation of eNOS and Akt, as well as inhibition of NO generation. All the effects are fully rescued by EC-specific over-expression of Kir2.1. A component of FIV that is Kir- independent is abrogated by blocking Ca2+-sensitive K+ channels. Kir2.1 has no effect on endothelium-independent and K+-induced vasodilation in denuded arteries. Kir2.1+/- mice also show increased mean blood pressure measured by carotid artery cannulation and increased microvascular resistance measured using a tail cuff. Importantly, blocking Kir channels also inhibits flow-induced vasodilation in human subcutaneous adipose microvessels. Conclusion: Endothelial Kir contribute to FIV of mouse mesenteric arteries via NO- dependent mechanism, whereas Ca2+-sensitive K+ channels mediate FIV via NO- independent pathway. Kir2 channels also regulate vascular resistance and blood pressure. Finally, Kir channels also contribute to FIV in human sub-cutaneous microvessels.