TY - JOUR
T1 - Dissecting VEGF-induced acute versus chronic vascular hyperpermeability
T2 - Essential roles of dimethylarginine dimethylaminohydrolase-1
AU - Wang, Ying
AU - Angom, Ramcharan Singh
AU - Kulkarni, Tanmay A.
AU - Hoeppner, Luke H.
AU - Pal, Krishnendu
AU - Wang, Enfeng
AU - Tam, Alexander
AU - Valiunas, Rachael A.
AU - Dutta, Shamit K.
AU - Ji, Baoan
AU - Jarzebska, Natalia
AU - Chen, Yingjie
AU - Rodionov, Roman N.
AU - Mukhopadhyay, Debabrata
N1 - 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
PY - 2021/10/22
Y1 - 2021/10/22
N2 - 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.
AB - 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.
KW - Cardiovascular medicine
KW - Molecular genetics
UR - http://www.scopus.com/inward/record.url?scp=85123108943&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85123108943&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2021.103189
DO - 10.1016/j.isci.2021.103189
M3 - Article
AN - SCOPUS:85123108943
SN - 2589-0042
VL - 24
JO - iScience
JF - iScience
IS - 10
M1 - 103189
ER -