BACKGROUND Diabetes mellitus is an important cardiovascular risk factor characterized by elevated plasma glucose levels. High glucose (HG) negatively influences endothelial cell (EC) function, which is characterized by the inability of ECs to respond to vascular endothelial growth factor (VEGF-A) stimulation. We aimed to identify potential strategies to improve EC function in diabetes. METHODS AND RESULTS Human umbilical cord endothelial cells (HUVECs) were subjected to hyperglycemic milieu by exposing cells to HG together with glucose metabolite, methylglyoxal (MG) in vitro. Hyperglycemic cells showed reduced chemotactic responses towards VEGF-A as revealed by Boyden chamber migration assays, indicating the development of "VEGF resistance" phenotype. Furthermore, HG/MG-exposed cells were defective in their general migratory and proliferative responses and were in a pro-apoptotic state. Mechanistically, the exposure to HG/MG resulted in reactive oxygen species (ROS) accumulation which is secondary to the impairment of thioredoxin (Trx) activity in these cells. Pharmacological and genetic targeting of Trx recapitulated VEGF resistance. Functional supplementation of Trx using thioredoxin mimetic peptides (TMP) reversed the HG/MG-induced ROS generation, improved the migration, proliferation, survival and restored VEGF-A-induced chemotaxis and sprouting angiogenesis of hyperglycemic ECs. Importantly, TMP treatment reduced ROS accumulation and improved VEGF-A responses of placental arterial endothelial cells isolated from gestational diabetes mellitus patients. CONCLUSIONS Our findings suggest a putative role for Trx in modulating EC function and its functional impairment in HG conditions contribute to EC dysfunction. Supplementation of TMP could be used as a novel strategy to improve endothelial cell function in diabetes.

中文翻译：

---

硫氧还蛋白模拟肽通过恢复VEGFR-2诱导的应答和改善细胞存活，减轻了高血糖诱导的内皮功能障碍。

背景技术糖尿病是重要的心血管危险因素，其特征在于血浆葡萄糖水平升高。高葡萄糖（HG）会对内皮细胞（EC）的功能产生负面影响，其特征是EC无法响应血管内皮生长因子（VEGF-A）刺激。我们旨在确定改善糖尿病EC功能的潜在策略。方法和结果通过将细胞与葡萄糖代谢产物甲基乙二醛（MG）一起暴露于HG，使人脐带内皮细胞（HUVEC）经受高血糖环境的治疗。博伊登室迁移试验表明，高血糖细胞对VEGF-A的趋化反应降低，表明“ VEGF抵抗”表型的发展。此外，暴露于HG / MG的细胞在其总体迁移和增殖反应中存在缺陷，并处于促凋亡状态。从机理上讲，暴露于HG / MG会导致活性氧（ROS）积累，其继发于这些细胞中硫氧还蛋白（Trx）活性的损害。Trx的药理和遗传靶向概括了VEGF的耐药性。使用硫氧还蛋白模拟肽（TMP）功能补充Trx可逆转HG / MG诱导的ROS生成，改善迁移，增殖，存活并恢复VEGF-A诱导的高血糖ECs趋化性和发芽血管生成。重要的是，TMP治疗减少了从妊娠糖尿病患者分离出的胎盘动脉内皮细胞的ROS积累并改善了VEGF-A反应。结论我们的研究结果提示Trx在调节EC功能中起推定作用，而其在HG条件下的功能损害会导致EC功能障碍。补充TMP可作为改善糖尿病内皮细胞功能的新策略。