PUBLICATION
Suppressing STAT3 activity protects the endothelial barrier from VEGF-mediated vascular permeability
- Authors
- Wang, L., Astone, M., Alam, S.K., Zhu, Z., Pei, W., Frank, D.A., Burgess, S.M., Hoeppner, L.H.
- ID
- ZDB-PUB-210922-15
- Date
- 2021
- Source
- Disease models & mechanisms 14(11): (Journal)
- Registered Authors
- Astone, Matteo, Burgess, Shawn, Hoeppner, Luke, Pei, Wuhong
- Keywords
- COVID-19, Pyrimethamine, Signal Transducer and Activator of Transcription 3 (STAT3), Vascular Endothelial Growth Factor (VEGF), Vascular Permeability, Zebrafish
- MeSH Terms
-
- Animals
- CRISPR-Cas Systems
- Capillary Permeability*
- Endothelium, Vascular/metabolism*
- Humans
- Intercellular Adhesion Molecule-1/metabolism
- Janus Kinase 2/metabolism
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Phosphorylation
- STAT3 Transcription Factor/genetics*
- STAT3 Transcription Factor/metabolism
- Signal Transduction
- Vascular Endothelial Growth Factor A/metabolism*
- Zebrafish
- PubMed
- 34542605 Full text @ Dis. Model. Mech.
Citation
Wang, L., Astone, M., Alam, S.K., Zhu, Z., Pei, W., Frank, D.A., Burgess, S.M., Hoeppner, L.H. (2021) Suppressing STAT3 activity protects the endothelial barrier from VEGF-mediated vascular permeability. Disease models & mechanisms. 14(11):.
Abstract
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 anti-microbial 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping