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10.1242/dmm.049029

http://scihub22266oqcxt.onion/10.1242/dmm.049029
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34542605!8592016!34542605
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suck abstract from ncbi


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pmid34542605      Dis+Model+Mech 2021 ; 14 (11): ä
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  • Suppressing STAT3 activity protects the endothelial barrier from VEGF-mediated vascular permeability #MMPMID34542605
  • Wang L; Astone M; Alam SK; Zhu Z; Pei W; Frank DA; Burgess SM; Hoeppner LH
  • Dis Model Mech 2021[Nov]; 14 (11): ä PMID34542605show ga
  • 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.
  • |*Capillary Permeability[MESH]
  • |Animals[MESH]
  • |CRISPR-Cas Systems[MESH]
  • |Endothelium, Vascular/*metabolism[MESH]
  • |Humans[MESH]
  • |Intercellular Adhesion Molecule-1/metabolism[MESH]
  • |Janus Kinase 2/metabolism[MESH]
  • |Mice[MESH]
  • |Mice, Inbred C57BL[MESH]
  • |Mice, Knockout[MESH]
  • |Phosphorylation[MESH]
  • |STAT3 Transcription Factor/*genetics/metabolism[MESH]
  • |Signal Transduction[MESH]
  • |Vascular Endothelial Growth Factor A/*metabolism[MESH]


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