Calcium-Dependent Ion Channels and the Regulation of Arteriolar Myogenic Tone.

Arterioles in the peripheral microcirculation regulate blood flow to and within tissues and organs, control capillary blood pressure and microvascular fluid exchange, govern peripheral vascular resistance, and contribute to the regulation of blood pressure. These important microvessels display pressure-dependent myogenic tone, the steady state level of contractile activity of vascular smooth muscle cells (VSMCs) that sets resting arteriolar internal diameter such that arterioles can both dilate and constrict to meet the blood flow and pressure needs of the tissues and organs that they perfuse. This perspective will focus on the Ca-dependent ion channels in the plasma and endoplasmic reticulum membranes of arteriolar VSMCs and endothelial cells (ECs) that regulate arteriolar tone. In VSMCs, Ca-dependent negative feedback regulation of myogenic tone is mediated by Ca-activated K (BK) channels and also Ca-dependent inactivation of voltage-gated Ca channels (VGCC). Transient receptor potential subfamily M, member 4 channels (TRPM4); Ca-activated Cl channels (CaCCs; TMEM16A/ANO1), Ca-dependent inhibition of voltage-gated K (K) and ATP-sensitive K (K) channels; and Ca-induced-Ca release through inositol 1,4,5-trisphosphate receptors (IPRs) participate in Ca-dependent positive-feedback regulation of myogenic tone. Calcium release from VSMC ryanodine receptors (RyRs) provide negative-feedback through Ca-spark-mediated control of BK channel activity, or positive-feedback regulation in cooperation with IPRs or CaCCs. In some arterioles, VSMC RyRs are silent. In ECs, transient receptor potential vanilloid subfamily, member 4 (TRPV4) channels produce Ca sparklets that activate IPRs and intermediate and small conductance Ca activated K (IK and sK) channels causing membrane hyperpolarization that is conducted to overlying VSMCs producing endothelium-dependent hyperpolarization and vasodilation. Endothelial IPRs produce Ca pulsars, Ca wavelets, Ca waves and increased global Ca levels activating EC sK and IK channels and causing Ca-dependent production of endothelial vasodilator autacoids such as NO, prostaglandin I and epoxides of arachidonic acid that mediate negative-feedback regulation of myogenic tone. Thus, Ca-dependent ion channels importantly contribute to many aspects of the regulation of myogenic tone in arterioles in the microcirculation.