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 Ca²⁺-dependent ion channels in the plasma and endoplasmic reticulum membranes of arteriolar VSMCs and endothelial cells (ECs) that regulate arteriolar tone. In VSMCs, Ca²⁺-dependent negative feedback regulation of myogenic tone is mediated by Ca²⁺-activated K⁺ (BK_Ca) channels and also Ca²⁺-dependent inactivation of voltage-gated Ca²⁺ channels (VGCC). Transient receptor potential subfamily M, member 4 channels (TRPM4); Ca²⁺-activated Cl^- channels (CaCCs; TMEM16A/ANO1), Ca²⁺-dependent inhibition of voltage-gated K⁺ (K_V) and ATP-sensitive K⁺ (K_ATP) channels; and Ca²⁺-induced-Ca²⁺ release through inositol 1,4,5-trisphosphate receptors (IP₃Rs) participate in Ca²⁺-dependent positive-feedback regulation of myogenic tone. Calcium release from VSMC ryanodine receptors (RyRs) provide negative-feedback through Ca²⁺-spark-mediated control of BK_Ca channel activity, or positive-feedback regulation in cooperation with IP₃Rs or CaCCs. In some arterioles, VSMC RyRs are silent. In ECs, transient receptor potential vanilloid subfamily, member 4 (TRPV4) channels produce Ca²⁺ sparklets that activate IP₃Rs and intermediate and small conductance Ca²⁺ activated K⁺ (IK_Ca and sK_Ca) channels causing membrane hyperpolarization that is conducted to overlying VSMCs producing endothelium-dependent hyperpolarization and vasodilation. Endothelial IP₃Rs produce Ca²⁺ pulsars, Ca²⁺ wavelets, Ca²⁺ waves and increased global Ca²⁺ levels activating EC sK_Ca and IK_Ca channels and causing Ca²⁺-dependent production of endothelial vasodilator autacoids such as NO, prostaglandin I₂ and epoxides of arachidonic acid that mediate negative-feedback regulation of myogenic tone. Thus, Ca²⁺-dependent ion channels importantly contribute to many aspects of the regulation of myogenic tone in arterioles in the microcirculation.