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A ligand-independent VEGFR2 signaling pathway limits angiogenic responses in diabetes.

ABSTRACT: Although vascular complications are a hallmark of diabetes, the molecular mechanisms that underlie endothelial dysfunction are unclear. We showed that reactive oxygen species generated from hyperglycemia promoted ligand-independent phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2). This VEGFR2 signaling occurred within the Golgi compartment and resulted in progressively decreased availability of VEGFR2 at the cell surface. Consequently, the responses of endothelial cells to exogenous VEGF in a mouse model of diabetes were impaired because of a specific deficiency of VEGFR2 at the cell surface, despite a lack of change in transcript abundance. Hyperglycemia-induced phosphorylation of VEGFR2 did not require intrinsic receptor kinase activity and was instead mediated by Src family kinases. The reduced cell surface abundance of VEGFR2 in diabetic mice was reversed by treatment with the antioxidant N-acetyl-L-cysteine, suggesting a causative role for oxidative stress. These findings uncover a mode of ligand-independent VEGFR2 signaling that can progressively lead to continuously muted responses to exogenous VEGF and limit angiogenic events.

SUBMITTER: Warren CM

PROVIDER: S-EPMC4030697 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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A ligand-independent VEGFR2 signaling pathway limits angiogenic responses in diabetes.

Warren Carmen M CM Ziyad Safiyyah S Briot Anaïs A Der Aaron A Iruela-Arispe M Luisa ML

Science signaling 20140107 307

Although vascular complications are a hallmark of diabetes, the molecular mechanisms that underlie endothelial dysfunction are unclear. We showed that reactive oxygen species generated from hyperglycemia promoted ligand-independent phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2). This VEGFR2 signaling occurred within the Golgi compartment and resulted in progressively decreased availability of VEGFR2 at the cell surface. Consequently, the responses of endothelial cells ...[more]

PMID: 24399295

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Project description:BACKGROUND:VEGF/VEGFR2 pathway is the central therapeutic target in anti-angiogenic treatment in multiple cancers. However, little work has been carried out concerning the pro-malignancy functions of VEGFR2 that are independent of its pro-angiogenesis effects in gastric cancer. Here, we demonstrated that VEGFR2 up-regulation in gastric cancer tissues was a prognostic marker for poor disease-free survival and overall survival of gastric cancer patients. METHODS:Immunohistochemistry was used to detect VEGFR2 and VTN expressions in specimens. Kaplan-Meier curves were constructed for survival analysis. Stably knockdown cell lines and overexpression cell lines were constructed by small interfering RNA and plasmids transfection. Real-time PCR and Western blot were used to confirm the expressions of target genes at both RNA and protein levels. Cell proliferation was measured by using Cell Counting Kit-8 and xenograft models. Microarray and bioinformatic analysis were also performed to identify the relationship between Vitronectin (VTN) and VEGFR2. RESULTS:When overexpressed in gastric cancer cells, VEGFR2 increased cellular proliferation and invasion in vitro and tumor formation in xenograft models. By using integrating microarray and bioinformatic analysis, we identifiedVTN as a downstream of VEGFR2 pathway. In gain- and loss-of function analysis in gastric cancer cells, VTN was further verified in consistent with VEGFR2 in expression levels and in regulating cell growth and motility in vitro and in vivo. Moreover, in gastric cancer samples, VTN was as also revealed as a poor prognostic factor. CONCLUSIONS:Our present findings defined a novel activity for VEGFR2 in promoting tumorogenicity, motility and indicating a poor survival in gastric cancer beyond its known pro-angiogenic effects. IMPLICATIONS:Our present findings defined a novel activity for VEGFR2 in promoting tumorogenicity, motility and indicating a poor survival in gastric cancer beyond its known pro-angiogenic effects, which may provide a new and valuable target for design of therapies for intervention and a new cognitive perspective for the anti-angiogenesis therapies.

Project description:BackgroundGinsenoside Rg1 was shown to exert ligand-independent activation of estrogen receptor (ER) via mitogen-activated protein kinase-mediated pathway. Our study aimed to delineate the mechanisms by which Rg1 activates the rapid ER signaling pathways.MethodsER-positive human breast cancer MCF-7 cells and ER-negative human embryonic kidney HEK293 cells were treated with Rg1 (10-12M, 10-8M), 17ß-estradiol (10-8M), or vehicle. Immunoprecipitation was conducted to investigate the interactions between signaling protein and ER in MCF-7 cells. To determine the roles of these signaling proteins in the actions of Rg1, small interfering RNA or their inhibitors were applied.ResultsRg1 rapidly induced ERα translocation to plasma membrane via caveolin-1 and the formation of signaling complex involving linker protein (Shc), insulin-like growth factor-I receptor, modulator of nongenomic activity of ER (MNAR), ERα, and cellular nonreceptor tyrosine kinase (c-Src) in MCF-7 cells. The induction of extracellular signal-regulated protein kinase and mitogen-activated protein kinase kinase (MEK) phosphorylation in MCF-7 cells by Rg1 was suppressed by cotreatment with small interfering RNA against these signaling proteins. The stimulatory effects of Rg1 on MEK phosphorylation in these cells were suppressed by both PP2 (Src kinase inhibitor) and AG1478 [epidermal growth factor receptor (EGFR) inhibitor]. In addition, Rg1-induced estrogenic activities, EGFR and MEK phosphorylation in MCF-7 cells were abolished by cotreatment with G15 (G protein-coupled estrogen receptor-1 antagonist). The increase in intracellular cyclic AMP accumulation, but not Ca mobilization, in MCF-7 cells by Rg1 could be abolished by G15.ConclusionGinsenoside Rg1 exerted estrogenic actions by rapidly inducing the formation of ER containing signalosome in MCF-7 cells. Additionally, Rg1 could activate EGFR and c-Src ER-independently and exert estrogenic effects via rapid activation of membrane-associated ER and G protein-coupled estrogen receptor.

Dataset Information

A ligand-independent VEGFR2 signaling pathway limits angiogenic responses in diabetes.

Publications

A ligand-independent VEGFR2 signaling pathway limits angiogenic responses in diabetes.

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