Aldosterone increases the expression and subcellular localization of SERCA2a and SERCA2b in the rat mesenteric artery

Aldosterone (Aldo), a mineralocorticoid hormone, modulates cardiovascular function by regulating the expression of intracellular Ca²⁺ handling proteins, among other effects. In rat resistance-sized mesenteric arteries (MA), Aldo treatment (10 nM, 24 h) upregulates both the L-type voltage-gated Ca²⁺ channel α_1C subunit (Ca_V1.2) and the Sarco/Endoplasmic Reticulum Ca²⁺ ATPase (SERCA pump), thereby increasing Sarcoplasmic Reticulum (SR) Ca²⁺ load. Two SERCA isoforms, SERCA2a and SERCA2b, are expressed in rat MA, but their specific physiological contributions to distinct intracellular Ca²⁺ signals, remain unclear. In this study, we characterized the relative abundance and subcellular distribution of SERCA2a and SERCA2b in rat MA, their regulation by Aldo, and the impact of Aldo-induced SERCA remodeling on local Ca²⁺ signals relevant to vascular function, such as Ca²⁺ sparks and Ca²⁺ waves. Aldo-treated MA smooth muscle cells (MASMC) exhibited increased Ca²⁺ spark frequency and a higher incidence of spontaneous Ca²⁺ waves. Aldo augmented both protein and mRNA levels of SERCA2a and SERCA2b, effects that were blocked by the mineralocorticoid receptor (MR) antagonist RU28318. Under control conditions, SERCA2a was predominantly localized in the perinuclear region, whereas SERCA2b was distributed across both subplasmalemmal and perinuclear regions. Aldo treatment increased the expression of both isoforms in all analyzed subcellular compartments (subplasmalemmal, cytoplasmic, and perinuclear), with a pronounced redistribution towards the subplasmalemmal region of MASMC. This shift in SERCA subcellular distribution likely contributes to enhanced superficial Ca²⁺ buffering and the ignition of Ca²⁺ sparks and Ca²⁺ waves. Furthermore, Aldo increased mRNA levels of mitochondrial transcription factors A and B2 (TFAM and TFB2M), previously implicated in SERCA regulation in human aorta, suggesting a transcriptional mechanism whereby MR activation of the SERCA2 gene is associated with increased TFAM and TFB2M expression. Collectively, these findings demonstrate for the first time that Aldo increases the expression and promotes the subplasmalemmal localization of SERCA2a and SERCA2b in MASMC. This remodeling underscores their critical role in maintaining the superficial Ca²⁺ buffering system and SR Ca²⁺ load to prevent pathological elevations in the intracellular Ca²⁺ concentration. Our results highlight the SERCA pump as a potential therapeutic target in hypertension associated with hyperaldosteronism.