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

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.

Effects of Flavonoid Supplementation on Nanomaterial-Induced Toxicity: A Meta-Analysis of Preclinical Animal Studies

“…In addition to apoptosis and DNA damage, previous studies showed that high amounts of NO ( 65 ), VEGF ( 66 ), and MPO ( 67 ) could be synthesized and released in cells in response to ROS and inflammation stimuli. All the enhanced NO ( 68 ), VEGF ( 69 ), and MPO ( 70 ) could mediate an increase in the permeability of vascular endothelium, which may result in the leakage of plasma albumin to tissues and cause hypoxia and edema of organs, ultimately triggering the function dysfunction and exacerbating the disease progression. Thus, NO, VEGF, and MPO were also therapeutic targets to prevent and treat nanomaterial-induced organ injuries.…”

In silico analysis and preclinical findings uncover potential targets of anti-cervical carcinoma and COVID-19 in laminarin, a promising nutraceutical

“…In the pathway analysis, we found that laminarin’s targets played a role in many cell signaling pathways related to COVID-19 and cervical carcinoma. The VEGF signaling pathway plays a vital role in the pathologies of COVID-19-associated pulmonary edema, sepsis, and acute lung injury ( Wang et al, 2021 ). A clinical comparison study among the COVID-19 patient categories found a significantly lower level of VEGF in the mildly symptomatic patients ( Tripathy et al, 2021 ).…”

Zinc Finger Protein-Activating Transcription Factor stimulates the angiogenesis and maturity of the neovessels in the Mouse With Hindlimb ischemia and Rat mesenteric Assay

“…The concept of molecular bridging is proposed to promote neovascularization and alleviate lower limb ischemia by promoting angiogenesis through angiogenic growth factors [1,2]. However, the perfusion pressure of neovessels could not be maintained due to the poor maturity and strong leaky effect on the exogenous gene therapy [3,4]. The previous results showed the transcription factor made from the ZFP can combine with the endogenous VEGF promoter to stimulate VEGF-A family and splice variants(such as121,145,165,189,206)expression in the Hy926 cell experiments [5].…”