Ca2+-Dependent Cl- Channels in Vascular Tone Regulation during Aging

Abstract

Identifying alterations caused by aging could be an important tool for improving the diagnosis of cardiovascular diseases. Changes in vascular tone regulation involve various mechanisms, like NO synthase activity, activity of the sympathetic nervous system, production of prostaglandin, endothelium-dependent relaxing, and contracting factors, etc. Surprisingly, Ca²⁺-dependent Cl^- channels (CaCCs) are involved in all alterations of the vascular tone regulation mentioned above. Furthermore, we discuss these mechanisms in the context of ontogenetic development and aging. The molecular and electrophysiological mechanisms of CaCCs activation on the cell membrane of the vascular smooth muscle cells (VSMC) and endothelium are explained, as well as the age-dependent changes that imply the activation or inhibition of CaCCs. In conclusion, due to the diverse intracellular concentration of chloride in VSMC and endothelial cells, the activation of CaCCs depends, in part, on intracellular Ca²⁺ concentration, and, in part, on voltage, leading to fine adjustments of vascular tone. The activation of CaCCs declines during ontogenetic development and aging. This decline in the activation of CaCCs involves a decrease in protein level, the impairment of Ca²⁺ influx, and probably other alterations in vascular tone regulation.

Keywords: Ca2+-dependent Cl− channels; TMEM16 protein family; aging; phospholipid scramblase; sympathetic nerve activity; vascular tone regulation.

Figure 1

The activation of CaCCs during agonist (norepinephrine)–induced contraction in the arteries of young (A) and aged (B) animals. (1) The release of Ca²⁺ from sarcoplasmic reticulum through IP₃R leads to activation of CaCCs. (2) The activation of CaCCs, together with the opening of L–VDCC (positive feedback, red arrow), causing fast depolarization of VSMC via the Cl⁻ efflux and Ca²⁺ influx (A). Age-dependent changes involve a decrease in the activity of CaCCs and L–VDCC, causing slower depolarization of VSMC (B). (3) Elevated [Ca²⁺]i activates CICR, and Ca²⁺ sparks provide additional stimulus for CaCCs activation in VSMC. (4) Cl⁻ efflux and Ca²⁺ influx increase depolarization and cause VSMC contraction. CaCCs and L–VDCC are inactivated through CaMKII. (5) Depending on the [Cl⁻]i, the activation of CaCCs on endothelium causes depolarization that increases NO release, or hyperpolarization that decreases NO release. L–VDCC are not expressed on endothelial cells (indicated by dashed lines), but the Ca²⁺ entry through L–VDCC in VSMC can pass to the endothelium through positions aligned with holes in the internal elastic lamina in amounts sufficient to activate Ca²⁺ signaling in endothelial cells [30]. TRPV4 channels are localized in nanoscale proximity of CaCCs and are activated together with CaCCs, leading to increased Ca²⁺ influx into the endothelial cell [31]. (6) The downregulation of CaCCs contributes to enhanced proliferation of VSMC. Solid arrows indicate stimulation, dashed arrows indicate inhibition, red arrow indicates positive feedback, purple arrows indicate Ca²⁺ currents, and orange arrows indicate Cl⁻ currents. Abbreviations: AC, adenylate cyclase; AR, adrenergic receptor; CaCCs, Ca²⁺–dependent Cl⁻ channels; cAMP, cyclic adenosine monophosphate; CIRC, Ca²⁺–induced Ca²⁺ release; CaMKII, Ca²⁺/calmodulin–dependent protein kinase II; EC, endothelial cell; eNOS, endothelial NO synthase; Gi, G protein–coupled receptor with αi subunit; Gq, G protein–coupled receptor with αq subunit; Gs, G protein–coupled receptor with αs subunit; IP₃, inositol triphosphate; IP₃R, IP₃ receptor; NO, nitric oxide; L–VDCC, L–type voltage–dependent Ca²⁺ channels; PKA, protein kinase A; PKG, protein kinase G; PLC, phospholipase C; RyR, ryanodine receptor; TRPV4, transient receptor potential cation channel subfamily V member 4; VSMC, vascular smooth muscle cell.