Dissecting VEGF-induced acute versus chronic vascular hyperpermeability: Essential roles of dimethylarginine dimethylaminohydrolase-1

Ying Wang, Ramcharan Singh Angom, Tanmay A. Kulkarni, Luke H. Hoeppner, Krishnendu Pal, Enfeng Wang, Alexander Tam, Rachael A. Valiunas, Shamit K. Dutta, Baoan Ji, Natalia Jarzebska, Yingjie Chen, Roman N. Rodionov, Debabrata Mukhopadhyay

Research output: Contribution to journalArticlepeer-review

Abstract

Vascular 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.

Original languageEnglish (US)
Article number103189
JournaliScience
Volume24
Issue number10
DOIs
StatePublished - Oct 22 2021

Keywords

  • Cardiovascular medicine
  • Molecular genetics

ASJC Scopus subject areas

  • General

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