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
Externally publishedYes

Bibliographical note

Funding Information:
We thank Dr. Laura Lewis-Tuffin at Mayo Clinic for assisting with the zebrafish imaging. We thank Drs. Vijay S. Madamsetty, Kequan Chen, Jian Zhu, Santanu Bhattacharya, and Pritam Das in Dr. Mukhopadhyay's laboratory at Mayo Clinic for assisting with the experiments and helpful discussions. We thank Dr. Xun Gong at Massachusetts Institute of Technology for the suggestions on the Matlab-based algorithm. This work was supported by National Institutes of Health [HL140411 and CA78383-20 to D.M. DK117910 to B.J. HL148339 to Y.W. ], Florida Department of Health Cancer Research Chair's Fund Florida [grant number#3J-02 to D.M.], American Heart Association [19CDA34700013 to Y.W.] and Mayo Clinic Center for Clinical and Translational Science (CCaTS) [Ted and Loretta Rogers Cardiovascular Career Development Award Honoring Hugh C. Smith to Y.W.], Department of Defense [W81XWH-20-1-0317 to B.J.], and a Grant-in-Aid of Research, Artistry and Scholarship Program Award #380634 from the Office of Vice President of Research at the University of Minnesota, the Elsa U. Pardee Foundation, and The Hormel Foundation to L.H.H. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Conceptualization, D.M. Y.W. L.H.H. R.SA, T.A.K.; Methodology, Y.W. R.SA, L.H.H. K.P.; Validation: Y.W. R.SA, T.A.K. L.H.H. E.W. S.D. K.P.; Resources: Y.C. R.N.R. N.J. B. Ji.; Software: T.A.K. A.T. and R.A.V.; Writing-Original Draft: Y.W.; Writing-Review & Editing: R.SA, T.A.K. L.H.H. R.N.R, Y.C and D.M.; Funding Acquisition: D.M. Y.W. B.J. L.H.H.; Supervision: D.M. The authors declare no competing interests.

Funding Information:
We thank Dr. Laura Lewis-Tuffin at Mayo Clinic for assisting with the zebrafish imaging. We thank Drs. Vijay S. Madamsetty, Kequan Chen, Jian Zhu, Santanu Bhattacharya, and Pritam Das in Dr. Mukhopadhyay’s laboratory at Mayo Clinic for assisting with the experiments and helpful discussions. We thank Dr. Xun Gong at Massachusetts Institute of Technology for the suggestions on the Matlab-based algorithm. This work was supported by National Institutes of Health [ HL140411 and CA78383-20 to D.M., DK117910 to B.J., HL148339 to Y.W., ], Florida Department of Health Cancer Research Chair’s Fund Florida [grant number# 3J-02 to D.M.], American Heart Association [ 19CDA34700013 to Y.W.] and Mayo Clinic Center for Clinical and Translational Science (CCaTS) [Ted and Loretta Rogers Cardiovascular Career Development Award Honoring Hugh C. Smith to Y.W.], Department of Defense [ W81XWH-20-1-0317 to B.J.], and a Grant-in-Aid of Research, Artistry and Scholarship Program Award # 380634 from the Office of Vice President of Research at the University of Minnesota , the Elsa U. Pardee Foundation , and The Hormel Foundation to L.H.H. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2021 The Authors

Keywords

  • Cardiovascular medicine
  • Molecular genetics

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