Journal
DISEASE MODELS & MECHANISMS
Volume 14, Issue 11, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dmm.049029
Keywords
Vascular permeability; VEGF; STAT3; Pyrimethamine; Zebrafish; COVID-19
Categories
Funding
- Office of Vice President of Research at the University of Minnesota [380634]
- American Cancer Society [129819-IRG-16-189-58-IRG81]
- Hormel Foundation
- Fifth District Eagles Cancer Telethon Postdoctoral Fellowship Award
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Vascular permeability triggered by inflammation or ischemia promotes edema and worsens disease progression, while VEGF plays a crucial role in regulating vascular barrier function. Targeting STAT3 can effectively reduce vascular permeability induced by VEGF.
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 STAT3deficient 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 VEGFinduced vascular permeability.
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