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FGF-dependent regulation of VEGF receptor 2 expression in mice.

ABSTRACT: Numerous studies have suggested a link between the angiogenic FGF and VEGF signaling pathways; however, the nature of this link has not been established. To evaluate this relationship, we investigated VEGF signaling in ECs with disrupted FGF signaling in vitro and in vivo. ECs lacking FGF signaling became unresponsive to VEGF, caused by downregulation of VEGF receptor 2 (VEGFR2) expression after reduced Vegfr2 enhancer activation. FGF mediated VEGFR2 expression via activation of Erk1/2. Transcriptional analysis revealed that Ets transcription factors controlled VEGFR2 expression in an FGF- and Erk1/2-dependent manner. Mice with defective FGF signaling exhibited loss of vascular integrity and reduced vascular morphogenesis. Thus, basal FGF stimulation of the endothelium is required for maintenance of VEGFR2 expression and the ability to respond to VEGF stimulation and accounts for the hierarchic control of vascular formation by FGFs and VEGF.

SUBMITTER: Murakami M

PROVIDER: S-EPMC3223828 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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FGF-dependent regulation of VEGF receptor 2 expression in mice.

Murakami Masahiro M Nguyen Loc T LT Hatanaka Kunihiko K Schachterle William W Chen Pei-Yu PY Zhuang Zhen W ZW Black Brian L BL Simons Michael M

The Journal of clinical investigation 20110701 7

Numerous studies have suggested a link between the angiogenic FGF and VEGF signaling pathways; however, the nature of this link has not been established. To evaluate this relationship, we investigated VEGF signaling in ECs with disrupted FGF signaling in vitro and in vivo. ECs lacking FGF signaling became unresponsive to VEGF, caused by downregulation of VEGF receptor 2 (VEGFR2) expression after reduced Vegfr2 enhancer activation. FGF mediated VEGFR2 expression via activation of Erk1/2. Transcri ...[more]

PMID: 21633168

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Project description:Non‑small cell lung cancer (NSCLC) accounts for over 80% of all diagnosed lung cancer cases. Lung cancer is the leading cause of cancer‑related deaths worldwide. Most NSCLC cells overexpress vascular endothelial growth factor‑A (VEGF‑A) which plays a pivotal role in tumour angiogenesis. Anti‑angiogenic therapies including VEGF‑A neutralisation have significantly improved the response rates, progression‑free survival and overall survival of patients with NSCLC. However, the median survival of these patients is shorter than 18 months, suggesting that NSCLC cells secrete VEGF‑independent angiogenic factors, which remain unknown. We aimed to explore these factors in human NSCLC cell lines, A549, Lu99 and EBC‑1 using serum‑free culture, to which only EBC‑1 cells could adapt. By mass spectrometry, we identified 1,007 proteins in the culture supernatant derived from EBC‑1 cells. Among the identified proteins, interleukin‑8 (IL‑8), macrophage migration inhibitory factor (MIF), galectin‑1, midkine (MK), IL‑18, galectin‑3, VEGF‑A, hepatoma‑derived growth factor (HDGF), osteopontin (OPN), connective tissue growth factor (CTGF) and granulin (GRN) are known to be involved in angiogenesis. Tube formation, neutralisation and RNA interference assays revealed that VEGF‑A and HDGF function as angiogenic factors in EBC‑1 cells. To confirm whether VEGF‑A and HDGF also regulate angiogenesis in the other NSCLC cell lines, we established a novel culture method. NSCLC cells were embedded in collagen gel and cultured three‑dimensionally. Tube formation, neutralisation and RNA interference assays using the three‑dimensional (3D) culture supernatant showed that VEGF‑A and HDGF were not angiogenic factors in Lu99 cells. By gene microarray in EBC‑1 and Lu99 cells, we identified 61 mRNAs expressed only in Lu99 cells. Among these mRNAs, brain‑derived neurotrophic factor (BDNF), fibroblast growth factor‑2 (FGF‑2) and FGF‑5 are known to be involved in angiogenesis. Tube formation and neutralisation assays clarified that FGF‑2 functions as an angiogenic factor in Lu99 cells. These results indicate that HDGF enhances VEGF‑dependent angiogenesis and that FGF‑2 is a VEGF‑independent angiogenic factor in human NSCLC cells.

Dataset Information

FGF-dependent regulation of VEGF receptor 2 expression in mice.

Publications

FGF-dependent regulation of VEGF receptor 2 expression in mice.

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