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Activated STAT3 is a mediator and biomarker of VEGF endothelial activation.

ABSTRACT: STAT3 plays important roles in cell proliferation and survival signaling and is often constitutively activated in transformed cells. In this study, we examined STAT3 activation in endothelial cells (EC) during angiogenic activation and therapeutic angiogenesis inhibition. VEGF stimulation of cultured EC induced STAT3 phosphorylation by a VEGFR2- and Src-dependent mechanism. FGF2 but not PlGF also induced EC STAT3 activation in vitro. Activated STAT3 mediated VEGF induction of EC Bcl-2 and contributed to VEGF protection of EC from apoptosis. In vivo, p-STAT3 was absent by immunohistological staining in the vascular EC of most normal mouse organs but was present in the vessels of mouse and human tumors. Tumor vascular p-STAT3 increased as tumors were induced to overexpress VEGF, indicating that VEGF is an activator of EC p-STAT3 in vivo. Tumor vascular p-STAT3 decreased during angiogenesis inhibition by antagonists of VEGF-VEGFR signaling, VEGF Trap and SU5416, indicating that VEGF contributed to the EC STAT3 activation seen in the tumors prior to treatment and that p-STAT3 may be used to monitor therapy. These studies show that p-STAT3 is a mediator and biomarker of endothelial activation that reports VEGF-VEGFR2 activity and may be useful for studying the pharmacodynamics of targeted angiogenesis inhibitors.

SUBMITTER: Chen SH

PROVIDER: S-EPMC2932444 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Activated STAT3 is a mediator and biomarker of VEGF endothelial activation.

Chen Shao-Hua SH Murphy Danielle A DA Lassoued Wiem W Thurston Gavin G Feldman Michael D MD Lee William M F WM

Cancer biology & therapy 20081211 12

STAT3 plays important roles in cell proliferation and survival signaling and is often constitutively activated in transformed cells. In this study, we examined STAT3 activation in endothelial cells (EC) during angiogenic activation and therapeutic angiogenesis inhibition. VEGF stimulation of cultured EC induced STAT3 phosphorylation by a VEGFR2- and Src-dependent mechanism. FGF2 but not PlGF also induced EC STAT3 activation in vitro. Activated STAT3 mediated VEGF induction of EC Bcl-2 and contri ...[more]

PMID: 18981713

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Project description: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, such as cancer, ischemic stroke, cardiovascular disease, retinal conditions, and COVID-19-associated pulmonary edema and sepsis, which often leads to acute lung injury, including acute respiratory distress syndrome. However, after initially stimulating permeability, VEGF subsequently mediates angiogenesis to repair damaged tissue. Consequently, understanding temporal molecular regulation of VEG-Finduced vascular permeability will facilitate developing therapeutics that achieve the delicate balance of inhibiting vascular permeability while preserving tissue repair. Here, we demonstrate that VEGF signals through signal transducer and activator of transcription 3 (STAT3) to promote vascular permeability. Specifically, we show that genetic STAT3 ablation reduces vascular permeability in STAT3-deficient endothelium of mice and VEGF-inducible zebrafish crossed with CRISPR/Cas9 generated genomic STAT3 knockout zebrafish. Importantly, STAT3 deficiency does not impair vascular development and function in vivo. We identify intercellular adhesion molecule 1 (ICAM-1) as a STAT3-dependent transcriptional regulator and show 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. Indeed, pharmacologically targeting STAT3 increases vascular barrier integrity using two additional compounds, atovaquone and C188-9. Collectively, our findings suggest that the VEGF, VEGFR-2, JAK2, and STAT3 signaling cascade regulates vascular barrier integrity, and inhibition of STAT3-dependent activity reduces VEGF-induced vascular permeability in vertebrate models.

Dataset Information

Activated STAT3 is a mediator and biomarker of VEGF endothelial activation.

Publications

Activated STAT3 is a mediator and biomarker of VEGF endothelial activation.

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