Vascular permeability triggered by inflammation or ischemia promotes edema, exacerbates disease progression and impairs tissue recovery. Vascular endothelial growth factor (VEGF) is a potent inducer of vascular permeability. VEGF plays an integral role in regulating vascular barrier function physiologically and in pathologies, including cancer, stroke, cardiovascular disease, retinal conditions and COVID-19-associated pulmonary edema, sepsis and acute lung injury. Understanding temporal molecular regulation of VEGF-induced vascular permeability will facilitate developing therapeutics to inhibit vascular permeability, while preserving tissue-restorative angiogenesis. Here, we demonstrate that VEGF signals through signal transducer and activator of transcription 3 (STAT3) to promote vascular permeability. We show that genetic STAT3 ablation reduces vascular permeability in STAT3-deficient endothelium of mice and VEGF-inducible zebrafish crossed with CRISPR/Cas9-generated Stat3 knockout zebrafish. Intercellular adhesion molecule 1 (ICAM-1) expression is transcriptionally regulated by STAT3, and VEGF-dependent STAT3 activation is regulated by JAK2. Pyrimethamine, an FDA-approved antimicrobial agent that inhibits STAT3-dependent transcription, substantially reduces VEGF-induced vascular permeability in zebrafish, mouse and human endothelium. Collectively, our findings suggest that VEGF/VEGFR-2/JAK2/STAT3 signaling regulates vascular barrier integrity, and inhibition of STAT3-dependent activity reduces VEGF-induced vascular permeability. This article has an associated First Person interview with the first author of the paper.
Bibliographical noteFunding Information:
We thank Dr Anna C. Sundborger-Lunna, Dr Veer Bhatt, Dr George Aslanidi and Dr Karina Kortova at The Hormel Institute for technically supporting the purification of the human STAT3 protein and sharing associated reagents. We are grateful to Christina E. Hernandez, Abbygail M. Coyle and Erin N. Dankert for their contributions to this work as Summer Undergraduate Research Experience interns. We appreciate the China-America Cancer Research Institute, Guangdong Medical University in Guangdong, China for supporting Zhu Zhu as a Visiting Scholar at The Hormel Institute. We thank Dr Jim Hu from the Hospital for Sick Children in Toronto, ON, Canada for generously sharing the pGL3-ICAM1 reporter vector. We thank The Hormel Institute and its staff for administrative, shared equipment, animal facility and institutional support. This work was supported by Grant-in-Aid of Research, Artistry and Scholarship Program Award #380634 from the Office of Vice President of Research at the University of Minnesota, Institutional Research Grant #129819-IRG-16-189-58-IRG81 from the American Cancer Society and the Hormel Foundation (to L.H.H.), as well as a Fifth District Eagles Cancer Telethon Postdoctoral Fellowship Award (to S.K.A.).
This work was supported by Grant-in-Aid of Research, Artistry and Scholarship Program Award #380634 from the Office of Vice President of Research at the University of Minnesota, Institutional Research Grant #129819-IRG-16-189-58-IRG81 from the American Cancer Society and the Hormel Foundation (to L.H.H.), as well as a Fifth District Eagles Cancer Telethon Postdoctoral Fellowship Award (to S.K.A.).
© 2021. Published by The Company of Biologists Ltd
- Vascular permeability
- Capillary Permeability
- Endothelium, Vascular/metabolism
- Intercellular Adhesion Molecule-1/metabolism
- Signal Transduction
- Mice, Inbred C57BL
- STAT3 Transcription Factor/genetics
- Vascular Endothelial Growth Factor A/metabolism
- Mice, Knockout
- CRISPR-Cas Systems
- Janus Kinase 2/metabolism
PubMed: MeSH publication types
- Research Support, Non-U.S. Gov't
- Journal Article