Abstract
Although voltage-gated Ca2+ channels (VGCC) are a major Ca2+ entry pathway in vascular smooth muscle cells (VSMCs), several other Ca2+-influx mechanisms exist and play important roles in vasoreactivity. One of these is store-operated Ca2+ entry (SOCE), mediated by an interaction between STIM1 and Orai1. Although SOCE is an important mechanism of Ca2+ influx in non-excitable cells (cells that lack VGCC); there is debate regarding the contribution of SOCE to regulate VSMC contractility and the molecular components involved. Our previous data suggest acid-sensing ion channel 1a (ASIC1a) is a necessary component of SOCE and vasoconstriction in small pulmonary arteries. However, it is unclear if ASIC1a similarly contributes to SOCE and vascular reactivity in systemic arteries. Considering the established role of Orai1 in mediating SOCE in the systemic circulation, we hypothesize the involvement of ASIC1a in SOCE and resultant vasoconstriction is unique to the pulmonary circulation. To test this hypothesis, we examined the roles of Orai1 and ASIC1a in SOCE- and endothelin-1 (ET-1)-induced vasoconstriction in small pulmonary and mesenteric arteries. We found SOCE is coupled to vasoconstriction in pulmonary arteries but not mesenteric arteries. In pulmonary arteries, inhibition of ASIC1a but not Orai1 attenuated SOCE- and ET-1-induced vasoconstriction. However, neither inhibition of ASIC1a nor Orai1 altered ET-1-induced vasoconstriction in mesenteric arteries. We conclude that SOCE plays an important role in pulmonary, but not mesenteric, vascular reactivity. Furthermore, in contrast to the established role of Orai1 in SOCE in non-excitable cells, the SOCE response in pulmonary VSMCs is largely mediated by ASIC1a.
Highlights
Vascular smooth muscle cell (VSMC) contraction and relaxation play an important role in the regulation of vascular resistance and blood pressure control
Since L-type Ca2+ channels are considered to be a major contributor to VSMC Ca2+ influx, we first determined the role of L-type voltage-gated Ca2+ channels (VGCC) to ET-1 induced vasoconstriction in small pulmonary and mesenteric arteries
The major findings of this study are that 1) the contribution of L-type VGCC to agonist-induced vasoconstriction in pulmonary and mesenteric arteries is minimal; 2) store-operated Ca2+ entry (SOCE) is functionally linked to vasoconstriction in pulmonary but not mesenteric arteries; and 3) acid-sensing ion channel 1a (ASIC1a) is the major contributor of SOCE and SOCE-induced vasoconstriction in pulmonary arteries; while Orai1 plays a minimal role in vasoconstriction in either bed
Summary
Vascular smooth muscle cell (VSMC) contraction and relaxation play an important role in the regulation of vascular resistance and blood pressure control. Ca2+ influx in VSMC is thought to be mediated primarily by L-type voltage-gated Ca2+ channels (VGCC), it has become increasingly clear that Ca2+ influx through non-selective cation channels (NSCC) plays an important role in regulating vascular tone These include 1) receptor-operated channels (ROCs) which are regulated by agonist-receptor interaction and downstream signal transduction [1]; 2) capacitative or store-operated channels (SOCs) which are activated by depletion of intracellular Ca2+ stores [2, 3]; 3) mechanosensitive or stretch-activated channels (SACs) which are activated by membrane stretch [4, 5]; and 4) constitutively active cation channels which are spontaneously active (reviewed in [6]). It is necessary to gain a better understanding of the heterogeneity that exists in Ca2+ signaling among vascular beds
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