High Glucose Treatment Induces Nuclei Aggregation of Microvascular Endothelial Cells via the foxo1a-klf2a Pathway.

IF 7.4 1区 医学 Q1 HEMATOLOGY
Xiaoning Wang, Xinyi Kang, Bowen Li, Changsheng Chen, Liping Chen, Dong Liu
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引用次数: 0

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) 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 foxo1a.

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 foxo1a downregulation in zebrafish 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.

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来源期刊
CiteScore
15.60
自引率
2.30%
发文量
337
审稿时长
2-4 weeks
期刊介绍: The journal "Arteriosclerosis, Thrombosis, and Vascular Biology" (ATVB) is a scientific publication that focuses on the fields of vascular biology, atherosclerosis, and thrombosis. It is a peer-reviewed journal that publishes original research articles, reviews, and other scholarly content related to these areas. The journal is published by the American Heart Association (AHA) and the American Stroke Association (ASA). The journal was published bi-monthly until January 1992, after which it transitioned to a monthly publication schedule. The journal is aimed at a professional audience, including academic cardiologists, vascular biologists, physiologists, pharmacologists and hematologists.
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