Vascular dysfunction is a common pathological basis for complications in individuals affected by diabetes. Previous studies have established that endothelial dysfunction is the primary contributor to vascular complications in type 2 diabetes (T2DM). However, the role of vascular smooth muscle cells (VSMCs) in vascular complications associated with T2DM is still not completely understood. The aim of this study is to explore the potential mechanisms associated with Ca2+ handling dysfunction and how this dysfunction contributes to diabetic vascular smooth muscle impairment. The results indicated that endothelium-dependent vasodilation was impaired in diabetic aortae, but endothelium-independent vasodilation was not altered. Various vasoconstrictors such as phenylephrine, U46619 and 5-HT could induce vasoconstriction in a concentration-dependent manner, such that the dose-response curve was parallel shifted to the right in diabetic aortae, compared to the control. Vasoconstrictions mediated by L-type calcium (Cav1.2) channels were attenuated in diabetic aortae, but effects mediated by store-operated calcium (SOC) channels were enhanced. Intracellular Ca2+ concentration ([Ca2+]i) in VSMCs was detected by Fluo-4 calcium fluorescent probes, and demonstrated that SOC-mediated Ca2+ entry was increased in diabetic VSMCs. VSMC-specific knockout of STIM1 genes decreased SOC-mediated and phenylephrine-induced vasoconstrictive response in mice aortae. Additionally, Orai1 expression was up-regulated, Cav1.2 expression was downregulated, and the phenotypic transformation of diabetic VSMCs was determined in diabetic aortae. The overexpression of Orai1 markedly promoted the OPN expression of VSMCs, whereas SKF96365 (SOC channel blocker) reversed the phenotypic transformation of diabetic VSMCs. Our results demonstrated that the vasoconstriction response of aortic smooth muscle was weakened in type 2 diabetic rats, which was related to the downregulation of the Cav1.2 channel and the up-regulation of the SOC channel signaling pathway.

中文翻译：

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Ca2 +处理异常会导致Zucker糖尿病脂肪大鼠的主动脉平滑肌收缩力受损。

血管功能障碍是受糖尿病影响的个体并发症的常见病理基础。先前的研究已经确定，内皮功能障碍是2型糖尿病（T2DM）中血管并发症的主要诱因。然而，血管平滑肌细胞（VSMC）在与T2DM相关的血管并发症中的作用仍未完全了解。这项研究的目的是探讨与Ca2 +处理功能障碍相关的潜在机制，以及这种功能障碍如何导致糖尿病性血管平滑肌损伤。结果表明，糖尿病主动脉内皮依赖性血管舒张功能受损，但内皮依赖性血管舒张功能未改变。各种血管收缩剂，例如去氧肾上腺素，U46619和5-HT可以以浓度依赖性的方式诱导血管收缩，因此与对照组相比，糖尿病主动脉的剂量反应曲线平行向右移动。L型钙（Cav1.2）通道介导的血管收缩在糖尿病主动脉中减弱，但由储存操作钙（SOC）通道介导的作用增强。通过Fluo-4钙荧光探针检测VSMC中的细胞内Ca2 +浓度（[Ca2 +] i），这表明在糖尿病VSMC中SOC介导的Ca2 +进入增加。VSMC特异性剔除STIM1基因可降低小鼠主动脉中SOC介导的和去氧肾上腺素诱导的血管收缩反应。此外，Orai1表达上调，Cav1.2表达下调，并在糖尿病主动脉中确定了糖尿病VSMC的表型转化。Orai1的过表达显着促进了VSMC的OPN表达，而SKF96365（SOC通道阻滞剂）逆转了糖尿病VSMC的表型转化。我们的结果表明，在2型糖尿病大鼠中，主动脉平滑肌的血管收缩反应减弱，这与Cav1.2通道的下调和SOC通道信号通路的上调有关。