Positive feedback influence of KCa3.1 channels on stimulated endothelial Ca2+ dynamics

Abstract

Dynamic Ca2+ transients underlie physiologic endothelial signaling and vasoregulation. Intermediate conductance Ca2+‐activated K+ channels (KCa3.1) are primary targets of endothelial Ca2+ signals in the arterial vasculature and their ablation results in hypertension. Localized Ca2+ events target KCa3.1 channels along the myoendothelial interface to elicit hyperpolarization and vasodilation. Here, we employ genetically altered KCa3.1 knockout mice (IK1−/−), confocal imaging, and custom analysis to assess possible feedback influence of these channels on the Ca2+ dynamics themselves. Basal endothelial Ca2+ dynamics were not different between IK1−/− and wild‐type (WT) mice (p < 0.05). However, acetylcholine (Ach) stimulated Ca2+ dynamics to a much greater degree in WT than in IK1−/− endothelium (sites 376 vs. 156; p < 0.05). Removal of extracellular Ca2+ reduced Ach‐induced Ca2+ dynamics in WT to the level of IK1−/−. These findings indicate that whereas KCa3.1 channels do not directly influence basal Ca2+ activity in mouse mesenteric artery endothelium, they exert substantial positive feedback under stimulated conditions, recruiting additional new Ca2+ sites and events along the intima. Overall, our findings suggest that KCa3.1 channels amplify endothelial Ca2+ dynamics, further enhancing arterial hyperpolarization and vasodilation. Supported by NIH R01 HL085887 and S10RR027535.