Low intravascular pressure activates endothelial cell TRPV4 channels, local Ca events, and IKCa channels, reducing arteriolar tone

Endothelial cell (EC) Ca-activated K channels (SKCa and IKCa channels) generate hyperpolarization that passes to the adjacent smooth muscle cells causing vasodilation. IKCa channels focused within EC projections toward the smoothmuscle cells are activated by spontaneous Ca events (Ca puffs/pulsars). We now show that transient receptor potential, vanilloid 4 channels (TRPV4 channels) also cluster within this microdomain and are selectively activated at low intravascular pressure. In arterioles pressurized to 80 mmHg, ECs generated low-frequency (∼2 min−1) inositol 1,4,5-trisphosphate receptor-based Ca events. Decreasing intraluminal pressure below 50 mmHg increased the frequency of EC Ca events twofold to threefold, an effect blocked with the TRPV4 antagonist RN1734. These discrete events represent both TRPV4-sparkletand nonsparklet-evoked Ca increases, which on occasion led to intracellular Ca waves. The concurrent vasodilation associatedwith increases in Ca event frequency was inhibited, and basal myogenic tone was increased, by either RN1734 or TRAM-34 (IKCa channel blocker), but not by apamin (SKCa channel blocker). These data show that intraluminal pressure influences an endothelial microdomain inversely to alter Ca event frequency; at low pressures the consequence is activation of EC IKCa channels and vasodilation, reducing themyogenic tone that underpins tissue blood-flow autoregulation.