文章基本信息

标题：Dissecting VEGF-induced acute versus chronic vascular hyperpermeability: Essential roles of dimethylarginine dimethylaminohydrolase-1
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作者：Ying Wang ; Ramcharan Singh Angom ; Tanmay A. Kulkarni 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2021
卷号：24
期号：10
页码：1-20
DOI：10.1016/j.isci.2021.103189
语种：English
出版社：Elsevier
摘要：SummaryVascular endothelial cell growth factor (VEGF) is a key regulator of vascular permeability. Herein we aim to understand how acute and chronic exposures of VEGF induce different levels of vascular permeability. We demonstrate that chronic VEGF exposure leads to decreased phosphorylation of VEGFR2 and c-Src as well as steady increases of nitric oxide (NO) as compared to that of acute exposure. Utilizing heat-inducible VEGF transgenic zebrafish (Danio rerio) and establishing an algorithm incorporating segmentation techniques for quantification, we monitored acute and chronic VEGF-induced vascular hyperpermeability in real time. Importantly, dimethylarginine dimethylaminohydrolase-1 (DDAH1), an enzyme essential for NO generation, was shown to play essential roles in both acute and chronic vascular permeability in cultured human cells, zebrafish model, and Miles assay. Taken together, our data reveal acute and chronic VEGF exposures induce divergent signaling pathways and identify DDAH1 as a critical player and potentially a therapeutic target of vascular hyperpermeability-mediated pathogenesis.Graphical abstractDisplay OmittedHighlights•Chronic VEGF exposure induces a different signaling pattern in endothelial cells•A novel algorithm can precisely quantify the vascular permeability in zebrafish model•DDAH1 acts as a novel mediator of VEGF-induced vascular hyperpermeabilityCardiovascular medicine; Molecular genetics