**6. Perspectives**

As mentioned above, SKCa is predominantly expressed in ECs, where it contributes to endothelium-derived hyperpolarization (EDH) of VSMC resulting in vasorelaxation of resistance arteries [108]. In a previous study, circulating aldosterone level was significantly higher in mice fed with high-fat diet (HFD) compared to lean mice; however, despite the restoration of endothelium-dependent vasodilation, eplerenone treatment further increased plasma aldosterone levels of HFD-fed obese mice [109]. Recently, using similar obese model, plasmatic aldosterone concentration was also augmented in male and female mice, whereas no change was found in endothelial cell-specific MR knockout mice (EC-MR-KO) subjected to HFD [110]. In males, obesity impaired NO-dependent vasodilation of resistance arteries, which was compensated by enhancement of EDH of VSMC along with an increase in mesenteric protein expression of SKCa3, while any change was observed in EC-MR-KO. On the other hand, in females, EDH component of VSMC relaxation was impaired, whereas the expression of SKCa3 remained unchanged in control and EC-MR-KO underwent to HFD [110]. Altogether, these results uncover distinct sex-specific mechanisms driving vascular dysfunc-

In VSMC, Ca2+ entry from the extracellular space involves a variety of plasmalemmal Ca2+ channels, which also involve the superfamily of transient receptor potential (TRP) channels, such as TRPC (canonical), TRPM (melastatin), TRPV (vanilloid), and TRPP (polycystin) [111]. Widely expressed in visceral and vascular SMC, changes in the expression and activity of these channels are implicated in a variety of physiological and pathophysiological consequences [112]. Although TRPM subfamily contains eight isoforms (TRPM1–8), which exhibit a variety of cation permeability, only TRPM6 and M7 seems to be Ca2+ and Mg2+ permeable. Interesting, aldosterone (100 nM) transiently upregulates mRNA TRPM7 expression in rat VSMC from 2 to 6 h after the onset of treatment, restoring to control level after 24 h of treatment [113]. However, up to date, no studies have been done to evaluate whether aldosterone

Originally thought to contribute solely to restoring Ca2+ concentration under store depletion, creating a capacitative Ca2+ entry, commonly termed as store-operated Ca2+ entry (SOCE), the role of SOCE is much more diverse than just refilling Ca2+ stores [114] but also contributing to vascular contractility, VSMC proliferation, and differentiation [112]. In addition, Ca2+ entry from the extracellular space may also occur through Ca2+-permeable store-independent channels, named as receptor-operated channels (ROC), which their activity depends on second messengers produced by downstream effectors from a vast array of G protein-coupled receptors [114]. TRPC subfamily comprises seven members (TRPC1–TRPC7), with the TRPC2 gene

Although TRPC1 seems to be the most abundant isoform expressed in rat mesenteric arteries, only the expression of TRPC6 was increased in deoxycorticosterone acetate (DOCA)-salt hypertensive rats [31]. Moreover, A7r5 cells treated with aldosterone (1 μM for 24 h) also displayed increased mRNA and protein levels of TRPC6 [31]. Accordingly, it was shown that coronary rings cultured for 7 days with aldosterone (100 nM), without fetal bovine

tion, suggesting personalized therapies to prevent vascular disorders.

**5.3. Transient receptor potential channels**

76 Calcium and Signal Transduction

modulates the expression of TRPV and TRPP channels.

being a pseudogene in humans [114].

Hypertension is a substantial public health problem, affecting 25% of the adult population in industrialized societies. This disorder is a major risk factor for many common causes of morbidity and mortality including stroke, myocardial infarction, congestive heart failure, and end-stage renal disease. Thus, substantial effort has been devoted to defining the pathogenesis of BP variation. Aldo, through the activation of MR in tubular epithelial cells, has a wellknown function on water balance and BP homeostasis. The renal hemodynamic consequences of excess mineralocorticoids—Na<sup>+</sup> and water retention and K<sup>+</sup> secretion—ultimately lead to hypertension. However, the kidney is no longer regarded as the primary site for mineralocorticoid modulation of BP. MR is consistently expressed in both ECs and VSMCs of blood vessels, and its activation by Aldo at pathological concentrations (10 nM) is associated with several types of vascular dysfunction, including atherosclerosis and hypertension. However, despite the recent understanding about the mechanisms involved in the activation of MR mainly in pathological conditions, further research is still required to determine the physiological role of MR-VSMCs in blood vessels.
