Contrasting Patterns of Agonist-induced Store-operated Ca2+ Entry and Vasoconstriction in Mesenteric Arteries and Aorta With Aging.

Aging is one of the strongest independent risk factors for vascular-related diseases, such as hypertension, diabetes mellitus, and atherosclerosis, through affecting vessel tone and arterial stiffness.1,2 Vascular smooth muscle cells (VSMCs) play a central role controlling the vascular tone and blood flow.3–5 In VSMCs, extracellular Ca2+ entry may be mediated through voltage-operated Ca2+ channels (VOCCs), receptor-operated Ca2+ channels,6 and/or store-operated Ca2+ channels (SOCCs). These pathways mediating Ca2+ entry regulate VSMCs contractility and vascular tone.7–9 In advanced aging, the balance of Ca2+ in cells is gradually lost, which may become a profound factor altering cellular physiological function.10–12 The activation of SOCCs is routinely evoked by Ca2+ store depletion, which is achieved by either Ca2+ release through IP3 receptors or by pharmacological inhibition of the sarco–endoplasmic reticulum (ER) Ca2+-ATPase.13 STIM1 and Orai1 have been well documented as the essential components of SOCCs.14–17 STIM1 serves as a Ca2+ store sensor located on the membrane of the ER. In the cell, store depletion induces STIM1 to oligomerize and move to ER/plasma membrane junctional domains, where it interacts with and activates Orai1 channels.18 Orai1 has been demonstrated to be a Ca2+-selective ion channel expressed in the plasma membrane. Opening Orai1 channels will mediate extracellular Ca2+ entry, which is commonly called store-operated Ca2+ entry (SOCE). In various tissue cells, SOCE is used as a key pathway to mediate longer-term cytosolic Ca2+ ([(Ca2+]i) signals and replenish intracellular Ca2+ stores.13,19,20 The down- or up-regulation of SOCE can result in the imbalance of intracellular Ca2+ homeostasis and subsequently alter blood vessel tone and diameter. Our previous study showed that changed SOCE in kidney mesangial cells with aging affected cell proliferation.12 However, whether SOCE and related vasoconstriction is changed in VSMCs from different vascular beds with aging remains to be determined. In this study, we investigated the difference of SOCE and SOCE-induced vasoconstriction in mesenteric artery and the aorta with aging. The results showed that both SOCE and SOCE-induced vasoconstriction was enhanced in mesenteric arteries but was declined in the aorta with advancing age. Alterations of STIM1 and Orai1 protein expression were coincident with the vasoconstriction change in mesenteric arteries and the aorta with aging.