Wang Xiaoning, Kang Xinyi, Li Bowen, Chen Changsheng, Chen Liping, Liu Dong
Research Center of Clinical Medicine, Affiliated Hospital (X.W., D.L.), Nantong University, China.
Obstetrics and Gynecology Department, The Second Affiliated Hospital of Nantong University, China (X.K., L.C., D.L.).
Arterioscler Thromb Vasc Biol. 2025 Mar;45(3):398-411. doi: 10.1161/ATVBAHA.124.321719. Epub 2025 Jan 30.
Hyperglycemia is a major contributor to endothelial dysfunction and blood vessel damage, leading to severe diabetic microvascular complications. Despite the growing body of research on the underlying mechanisms of endothelial cell (EC) dysfunction, the available drugs based on current knowledge fall short of effectively alleviating these complications. Therefore, our endeavor to explore novel insights into the cellular and molecular mechanisms of endothelial dysfunction is crucial for the field.
In this study, we performed a high-resolution imaging and time-lapse imaging analysis of the behavior of ECs in ) zebrafish embryos upon high glucose treatment. Genetic manipulation and chemical biology approaches were utilized to analyze the underlying mechanism of high glucose-induced nuclei aggregation and aberrant migration of zebrafish ECs and cultured human ECs. Bioinformatical analysis of single-cell RNA-sequencing data and molecular biological techniques was performed to identify the target genes of .
In this study, we observed that the high glucose treatment resulted in nuclei aggregation of ECs in zebrafish intersegmental vessels. Additionally, the aberrant migration of microvascular ECs in high glucose-treated embryos, which might be a cause of nuclei aggregation, was discovered. High glucose induced aggregation of vascular endothelial nuclei via downregulation in zebrafish embryos. Then, we revealed that high glucose resulted in the downregulation of expression and increased the expression of its direct downstream effector, , through which the aberrant migration and aggregation of vascular endothelial nuclei were caused.
High glucose treatment caused the nuclei of ECs to aggregate in vivo, which resembles the crowded nuclei of ECs in microaneurysms. High glucose suppresses expression and increases the expression of its downstream effector, , thereby causing the aberrant migration and aggregation of vascular endothelial nuclei. Our findings provide a novel insight into the mechanism of microvascular complications in hyperglycemia.
高血糖是导致内皮功能障碍和血管损伤的主要因素，可引发严重的糖尿病微血管并发症。尽管关于内皮细胞（EC）功能障碍潜在机制的研究日益增多，但基于现有认知的可用药物仍无法有效缓解这些并发症。因此，我们致力于探索内皮功能障碍细胞和分子机制的新见解，这对该领域至关重要。
在本研究中，我们对高糖处理的斑马鱼胚胎中的EC行为进行了高分辨率成像和延时成像分析。利用基因操作和化学生物学方法分析高糖诱导的斑马鱼EC和培养的人EC细胞核聚集及异常迁移的潜在机制。对单细胞RNA测序数据进行生物信息学分析并运用分子生物学技术来鉴定……的靶基因。
在本研究中，我们观察到高糖处理导致斑马鱼节间血管中EC细胞核聚集。此外，还发现高糖处理胚胎中微血管EC的异常迁移，这可能是细胞核聚集的一个原因。高糖通过下调斑马鱼胚胎中的……诱导血管内皮细胞核聚集。然后，我们揭示高糖导致……表达下调并增加其直接下游效应物……的表达，由此引起血管内皮细胞核的异常迁移和聚集。
高糖处理导致体内EC细胞核聚集，这类似于微动脉瘤中EC拥挤的细胞核。高糖抑制……表达并增加其下游效应物……的表达，从而导致血管内皮细胞核的异常迁移和聚集。我们的研究结果为高血糖微血管并发症的机制提供了新见解。
