Dysfunction in the SOCE/EDH-mediated vasorelaxation of mesenteric arteries impairs intestinal barrier integrity in...

Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder with an incompletely understood pathogenesis. Although dysregulation of the enteric nervous system, mucosal barrier, brain-gut axis, and immune-microbiota interactions has been extensively investigated, the contribution of intestinal microcirculatory dysfunction remains largely unclear. In this study, a water avoidance stress (WAS) model was used to induce diarrhea-predominant IBS (IBS-D) in mice, and endothelium-dependent vasorelaxation in mesenteric small resistance arteries was assessed using wire myography. We found that acetylcholine (ACh)-induced endothelium-dependent hyperpolarization (EDH)-mediated vasorelaxation was significantly impaired in WAS-treated mice. This impairment was transient and reversible on days 1 and 3 post-WAS but became sustained by day 10. In contrast, intestinal barrier integrity was preserved on day 1, began to deteriorate by day 3, and was markedly disrupted by day 10, indicating that EDH dysfunction precedes mucosal barrier impairment. Mechanistically, EDH dysfunction was selectively associated with dysregulated store-operated calcium entry (SOCE), whereas ryanodine receptors, inositol 1,4,5-trisphosphate receptors, intermediate- and small-conductance Ca²⁺-activated K⁺ channels, and TRPV4 channels were not involved. Norepinephrine-induced vasoconstriction was enhanced on day 10, while sodium nitroprusside-induced vasorelaxation remained unaffected. Notably, zinc supplementation restored ACh-induced EDH-mediated vasorelaxation in WAS-treated arteries via Zn²⁺ signaling and activation of the zinc sensitive receptor (ZnR), suggesting a potential therapeutic strategy. Collectively, these findings demonstrate that SOCE-dependent EDH impairment contributes to intestinal microcirculatory dysfunction, leading to compromised mucosal perfusion and barrier integrity in IBS-D. Targeting Zn²⁺ signaling/ZnR to restore vascular function may represent a promising therapeutic approach for this disorder.