Zhang Luyun, Rong Shaoya, Wang Jianxin, Wan Hanxing, Xu Feng, Dong Hui
Department of Pharmacology, School of Pharmacy, Qingdao University Medical College, #1 Ningde Road, Qingdao, 266073, China.
Department of Critical Care Medicine, Health Management Center, University of Electronic Science and Technology of China Sichuan Provincial People's Hospital, Chengdu, 610000, Sichuan, China.
Heliyon. 2024 Jul 6;10(14):e33994. doi: 10.1016/j.heliyon.2024.e33994. eCollection 2024 Jul 30.
Although the store-operated Ca entry (SOCE) plays a critical role in maintaining Ca homeostasis in vascular endothelial cells (VECs), its role in regulating endothelium-dependent hyperpolarization (EDH)-mediated vasorelaxation is largely unknown. Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are the most common gastrointestinal disorders with no effective cures. The present study applied N,N,N',N'-tetrakis (2-pyridylmethyl)ethylenediamine (TPEN) as a Ca chelator in the endoplasmic reticulum (ER) to study the SOCE/EDH-mediated vasorelaxation of micro-arteries and their involvements in the pathogenesis of IBD and IBS. Human submucosal arterioles and the second-order branch of 6-8 weeks male C57BL/6 mouse mesenteric arterioles were used, and TPEN-induced vasorelaxation was recorded by Danish DMT520A microvascular measuring system. The mice were fed water with 2.5 % dextran sulfate sodium for 7 days to induce mouse model of ulcerative colitis, and water avoidance stress was used to induce mouse model of IBS. The statistical significance of differences in the means of experimental groups was determined using a -test for two groups or one-way ANOVA for more than two groups. TPEN concentration-dependently induced vasorelaxation of human colonic submucosal arterioles and the second-order branch of murine mesenteric arteries in endothelium-dependent manner. TPEN-induced vasorelaxation was much greater in the arteries pre-constricted by noradrenaline than those by high K. While TPEN-induced vasorelaxation was unaffected by inhibitors of NO and PGI, it was significantly inhibited by the selective inhibitors of IK and SK channels but was potentiated by their activator. Moreover, TPEN-induced vasorelaxation was attenuated by selective inhibitors of NCX, NKA, SOCE, STIM translocation and Orai transportation. Finally, TPEN-induced vasorelaxation via SOCE/EDH was impaired in colitic mice but remained intact in IBS mice. Interestingly, TPEN could rescue vagus neurotransmitter ACh-induced vasorelaxation that was impaired in IBS mice. Therefore, since TPEN-induced SOCE/EDH-mediated vasorelaxation of mesenteric arteries is well-preserved to be able to rescue ACh-induced vasorelaxation impaired in IBS, TPEN has therapeutic potentials for IBS.
尽管储存式钙内流（SOCE）在维持血管内皮细胞（VECs）的钙稳态中起关键作用，但其在调节内皮依赖性超极化（EDH）介导的血管舒张中的作用仍 largely 未知。炎症性肠病（IBD）和肠易激综合征（IBS）是最常见的胃肠道疾病，尚无有效治愈方法。本研究应用 N,N,N',N'-四（2-吡啶甲基）乙二胺（TPEN）作为内质网（ER）中的钙螯合剂，以研究 SOCE/EDH 介导的微动脉血管舒张及其在 IBD 和 IBS 发病机制中的作用。使用人黏膜下小动脉和 6-8 周龄雄性 C57BL/6 小鼠肠系膜小动脉的二级分支，并通过丹麦 DMT520A 微血管测量系统记录 TPEN 诱导的血管舒张。给小鼠喂食含 2.5%葡聚糖硫酸钠的水 7 天以诱导溃疡性结肠炎小鼠模型，采用水回避应激诱导 IBS 小鼠模型。使用两组的 t 检验或多于两组的单因素方差分析确定实验组均值差异的统计学显著性。TPEN 以浓度依赖性方式以内皮依赖性方式诱导人结肠黏膜下小动脉和小鼠肠系膜动脉二级分支的血管舒张。TPEN 诱导的血管舒张在去甲肾上腺素预收缩的动脉中比在高钾预收缩的动脉中更大。虽然 TPEN 诱导的血管舒张不受 NO 和 PGI 抑制剂的影响，但它被 IK 和 SK 通道的选择性抑制剂显著抑制，但被其激活剂增强。此外，TPEN 诱导的血管舒张被 NCX、NKA、SOCE、STIM 易位和 Orai 转运的选择性抑制剂减弱。最后，TPEN 通过 SOCE/EDH 诱导的血管舒张在结肠炎小鼠中受损，但在 IBS 小鼠中保持完整。有趣的是，TPEN 可以挽救在 IBS 小鼠中受损的迷走神经递质 ACh 诱导的血管舒张。因此，由于 TPEN 诱导的肠系膜动脉 SOCE/EDH 介导的血管舒张保存完好，能够挽救在 IBS 中受损的 ACh 诱导的血管舒张，TPEN 对 IBS 具有治疗潜力。
