BACKGROUND

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.

METHODS

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 .

RESULTS

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.

CONCLUSIONS

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.