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  • Suppressing STAT3 activity protects the endothelial barrier from VEGF-mediated vascular permeability.

Suppressing STAT3 activity protects the endothelial barrier from VEGF-mediated vascular permeability.

Disease models & mechanisms (2021-09-21)
Li Wang, Matteo Astone, Sk Kayum Alam, Zhu Zhu, Wuhong Pei, David A Frank, Shawn M Burgess, Luke H Hoeppner
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 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
STAT3 Inhibitor XIII, C188-9, The Stat3 Inhibitor XIII, C188-9 controls the biological activity of Stat3. This small molecule/inhibitor is primarily used for Phosphorylation & Dephosphorylation applications.
Sigma-Aldrich
Anti-Rabbit IgG (H+L), F(ab′)2 fragment, CF488A antibody produced in goat, ~2 mg/mL, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Atovaquone, ≥98% (HPLC)
Sigma-Aldrich
Tyrphostin AG 490, solid