Aldosterone-Induced Sarco/Endoplasmic Reticulum Ca Pump Upregulation Counterbalances Ca1.2-Mediated Ca Influx in Mesenteric Arteries

In mesenteric arteries (MAs), aldosterone (ALDO) binds to the endogenous mineralocorticoid receptor (MR) and increases the expression of the voltage-gated L-type Ca1.2 channel, an essential ion channel for vascular contraction, sarcoplasmic reticulum (SR) Ca store refilling, and Ca spark generation. In mesenteric artery smooth muscle cells (MASMCs), Ca influx through Ca1.2 is the indirect mechanism for triggering Ca sparks. This process is facilitated by plasma membrane-sarcoplasmic reticulum (PM-SR) nanojunctions that drive Ca from the extracellular space into the SR via Sarco/Endoplasmic Reticulum Ca (SERCA) pump. Ca sparks produced by clusters of Ryanodine receptors (RyRs) at PM-SR nanodomains, decrease contractility by activating large-conductance Ca-activated K channels (BK channels), which generate spontaneous transient outward currents (STOCs). Altogether, Ca1.2, SERCA pump, RyRs, and BK channels work as a functional unit at the PM-SR nanodomain, regulating intracellular Ca and vascular function. However, the effect of the ALDO/MR signaling pathway on this functional unit has not been completely explored. Our results show that short-term exposure to ALDO (10 nM, 24 h) increased the expression of Ca1.2 in rat MAs. The depolarization-induced Ca entry increased SR Ca load, and the frequencies of both Ca sparks and STOCs, while [Ca] and vasoconstriction remained unaltered in Aldo-treated MAs. ALDO treatment significantly increased the mRNA and protein expression levels of the SERCA pump, which counterbalanced the augmented Ca1.2-mediated Ca influx at the PM-SR nanodomain, increasing SR Ca content, Ca spark and STOC frequencies, and opposing to hyperpolarization-induced vasoconstriction while enhancing Acetylcholine-mediated vasorelaxation. This work provides novel evidence for short-term ALDO-induced upregulation of the functional unit comprising Ca1.2, SERCA2 pump, RyRs, and BK channels; in which the SERCA pump buffers ALDO-induced upregulation of Ca entry at the superficial SR-PM nanodomain of MASMCs, preventing ALDO-triggered depolarization-induced vasoconstriction and enhancing vasodilation. Pathological conditions that lead to SERCA pump downregulation, for instance, chronic exposure to ALDO, might favor the development of ALDO/MR-mediated augmented vasoconstriction of mesenteric arteries.