PUBLICATION
High Glucose Treatment Induces Nuclei Aggregation of Microvascular Endothelial Cells via the foxo1a-klf2a Pathway
- Authors
- Wang, X., Kang, X., Li, B., Chen, C., Chen, L., Liu, D.
- ID
- ZDB-PUB-250131-2
- Date
- 2025
- Source
- Arteriosclerosis, Thrombosis, and Vascular Biology : (Journal)
- Registered Authors
- Liu, Dong
- Keywords
- animals, biology, endothelial cells, glucose, humans
- Datasets
- GEO:GSE276251
- MeSH Terms
-
- Kruppel-Like Transcription Factors*/genetics
- Kruppel-Like Transcription Factors*/metabolism
- Signal Transduction*
- Human Umbilical Vein Endothelial Cells/drug effects
- Human Umbilical Vein Endothelial Cells/metabolism
- Forkhead Box Protein O1/genetics
- Forkhead Box Protein O1/metabolism
- Zebrafish*
- Hyperglycemia/genetics
- Hyperglycemia/metabolism
- Cell Nucleus*/metabolism
- Gene Expression Regulation, Developmental
- Glucose*/metabolism
- Glucose*/pharmacology
- Animals
- Animals, Genetically Modified
- Microvessels/drug effects
- Microvessels/metabolism
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Endothelial Cells*/drug effects
- Endothelial Cells*/metabolism
- Endothelial Cells*/pathology
- Cell Movement*/drug effects
- Cells, Cultured
- Humans
- PubMed
- 39882604 Full text @ Arterio., Thromb., and Vas. Bio.
Citation
Wang, X., Kang, X., Li, B., Chen, C., Chen, L., Liu, D. (2025) High Glucose Treatment Induces Nuclei Aggregation of Microvascular Endothelial Cells via the foxo1a-klf2a Pathway. Arteriosclerosis, Thrombosis, and Vascular Biology. :.
Abstract
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 Tg(kdrl:ras-mCherry::fli1a:nGFP) zebra fish 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 zebra fish 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 foxo1a.
Results In this study, we observed that the high glucose treatment resulted in nuclei aggregation of ECs in zebra fish 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 foxo1a downregulation in zebra fish embryos. Then, we revealed that high glucose resulted in the downregulation of foxo1a expression and increased the expression of its direct downstream effector, klf2a, 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 foxo1a expression and increases the expression of its downstream effector, klf2a, 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping