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Ghrelin Decreases Angiogenesis, HIF-1α and VEGF Protein Levels in Chronic Hypoxia in Lung Tissue of Male Rats.

ABSTRACT: Hypoxia is a condition of decreased availability of oxygen. When cells are exposed to a low oxygen environment, they impel the hypoxia responses to adapt to new situation. The hypoxia response leads to the activation of various cellular signaling pathways. The aim of this study was to evaluate the effect of ghrelin on angiogenesis, Hypoxia-Inducible-Factor-1α (HIF-1) and Vascular endothelial growth factor (VEGF) levels in normobaric hypoxia situation.Twenty four animals were divided into 4 groups (n=6): control (C), ghrelin (Gh), hypoxia (H), and hypoxic animals that received ghrelin (H+Gh). Hypoxia (11%) was induced by an Environmental Chamber System GO2 Altitude. Animals in ghrelin groups received a subcutaneous injection of ghrelin (150 μg/kg/day) for 14 days.Our results showed that hypoxia significantly (p<0.05) increased angiogenesis without any significant changes on HIF-1 and VEGF levels, whereas ghrelin significantly (p<0.05) decreased angiogenesis, expression of HIF-1 and VEGF in this condition. Ghrelin administration did not show any significant changes in normal conditions.Ghrelin had no effect on angiogenesis, expression of HIF-1 and VEGF in normal oxygen conditions but it reduced angiogenesis process in lung tissue with reducing the level of HIF and VEGF in hypoxic condition. Therefore, effect of ghrelin on angiogenesis could be related to blood oxygen level.

SUBMITTER: Mirzaei Bavil F

PROVIDER: S-EPMC4616885 | biostudies-other | 2015 Sep

REPOSITORIES: biostudies-other

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Ghrelin Decreases Angiogenesis, HIF-1α and VEGF Protein Levels in Chronic Hypoxia in Lung Tissue of Male Rats.

Mirzaei Bavil Fariba F Alipour Mohammad Reza MR Keyhanmanesh Rana R Alihemmati Alireza A Alihemmati Alireza A Ghiyasi Rafigheh R Mohaddes Gisou G

Advanced pharmaceutical bulletin 20150919 3

<h4>Purpose</h4>Hypoxia is a condition of decreased availability of oxygen. When cells are exposed to a low oxygen environment, they impel the hypoxia responses to adapt to new situation. The hypoxia response leads to the activation of various cellular signaling pathways. The aim of this study was to evaluate the effect of ghrelin on angiogenesis, Hypoxia-Inducible-Factor-1α (HIF-1) and Vascular endothelial growth factor (VEGF) levels in normobaric hypoxia situation.<h4>Methods</h4>Twenty four a ...[more]

PMID: 26504752

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Project description:IntroductionCarcinoma-associated fibroblasts (CAFs) play a pivotal role in cancer progression by contributing to invasion, metastasis and angiogenesis. Solid tumors possess a unique microenvironment characterized by local hypoxia, which induces gene expression changes and biological features leading to poor outcomes. Hypoxia Inducible Factor 1 (HIF-1) is the main transcription factor that mediates the cell response to hypoxia through different mechanisms that include the regulation of genes strongly associated with cancer aggressiveness. Among the HIF-1 target genes, the G-protein estrogen receptor (GPER) exerts a stimulatory role in diverse types of cancer cells and in CAFs.MethodsWe evaluated the regulation and function of the key angiogenic mediator vascular endothelial growth factor (VEGF) in CAFs exposed to hypoxia. Gene expression studies, Western blotting analysis and immunofluorescence experiments were performed in CAFs and breast cancer cells in the presence of cobalt chloride (CoCl₂) or cultured under low oxygen tension (2% O₂), in order to analyze the involvement of the HIF-1α/GPER signaling in the biological responses to hypoxia. We also explored the role of the HIF-1α/GPER transduction pathway in functional assays like tube formation in human umbilical vein endothelial cells (HUVECs) and cell migration in CAFs.ResultsWe first determined that hypoxia induces the expression of HIF-1α and GPER in CAFs, then we ascertained that the HIF-1α/GPER signaling is involved in the regulation of VEGF expression in breast cancer cells and in CAFs exposed to hypoxia. We also assessed by ChIP assay that HIF-1α and GPER are both recruited to the VEGF promoter sequence and required for VEGF promoter stimulation upon hypoxic condition. As a biological counterpart of these findings, conditioned medium from hypoxic CAFs promoted tube formation in HUVECs in a HIF-1α/GPER dependent manner. The functional cooperation between HIF-1α and GPER in CAFs was also evidenced in the hypoxia-induced cell migration, which involved a further target of the HIF-1α/GPER signaling like connective tissue growth factor (CTGF).ConclusionsThe present results provide novel insight into the role elicited by the HIF-1α/GPER transduction pathway in CAFs towards the hypoxia-dependent tumor angiogenesis. Our findings further extend the molecular mechanisms through which the tumor microenvironment may contribute to cancer progression.

Dataset Information

Ghrelin Decreases Angiogenesis, HIF-1α and VEGF Protein Levels in Chronic Hypoxia in Lung Tissue of Male Rats.

Publications

Ghrelin Decreases Angiogenesis, HIF-1α and VEGF Protein Levels in Chronic Hypoxia in Lung Tissue of Male Rats.

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