AUTHOR=Zhang Lu Yun , Chen Xiong Ying , Dong Hui , Xu Feng 

TITLE=Cyclopiazonic Acid-Induced Ca2+ Store Depletion Initiates Endothelium-Dependent Hyperpolarization-Mediated Vasorelaxation of Mesenteric Arteries in Healthy and Colitis Mice

JOURNAL=Frontiers in Physiology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2021.639857

DOI=10.3389/fphys.2021.639857

ISSN=1664-042X

ABSTRACT=<p><bold>Purposes</bold>: Since the role of store-operated calcium entry (SOCE) in endothelium-dependent hyperpolarization (EDH)-mediated vasorelaxation of mesenteric arteries in health and colitis is not fully understood, cyclopiazonic acid (CPA), a specific inhibitor of the sarco(endo) plasmic reticulum calcium-ATPases (SERCA), was used as a SOCE activator to investigate its role in normal mice and its alteration in colitis mice.</p><p><bold>Methods</bold>: The changes in Ca<sup>2+</sup> signaling in vascular endothelial cells (VEC) were examined by single cell Ca<sup>2+</sup> imaging and tension of mesenteric arteries in response to CPA were examined using Danish DMT520A microvascular measuring system.</p><p><bold>Results</bold>: CPA activated the SOCE through depletion of the endoplasmic reticulum (ER) Ca<sup>2+</sup> in endothelial cells. CPA had a concentration-dependent vasorelaxing effect in endothelium-intact mesenteric arteries, which was lost after endothelial removal. Both nitric oxide (NO) and prostacyclin (PGI<sub>2</sub>) inhibitors did not affect CPA-induced vasorelaxation; however, after both NO and PGI<sub>2</sub> were inhibited, K<sub>Ca</sub> channel blocker [10 mM tetraethylammonium chloride (TEA)] inhibited CPA-induced vasorelaxation while K<sub>Ca</sub> channel activator (0.3 μM SKA-31) promoted it. Two SOCE blockers [30 μM SKF96365 and 100 μM flufenamic acid (FFA)], and an Orai channel blocker (30 μM GSK-7975A) inhibited this vasorelaxation. The inhibition of both Na<sup>+</sup>/K<sup>+</sup>-ATPase (NKA) and Na<sup>+</sup>/Ca<sup>2+</sup>-exchange (NCX) also inhibited CPA-induced vasorelaxation. Finally, the CPA involved in EDH-induced vasorelaxation by the depletion of ER Ca<sup>2+</sup> of mesenteric arteries was impaired in colitis mice.</p><p><bold>Conclusion</bold>: Depletion of ER Ca<sup>2+</sup> by CPA induces a vasorelaxation of mesenteric arteries that is mediated through EDH mechanism and invokes the activation of SOCE. The CPA-induced endothelium-dependent dilation is impaired in colitis which may limit blood perfusion to the intestinal mucosa.</p>