Impairment of hypoxia-induced angiogenesis by LDL involves a HIF-centered signaling network linking inflammatory TNFα and angiogenic VEGF.
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ABSTRACT:
SUBMITTER: Jin F
PROVIDER: S-EPMC6366960 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Emerging evidence indicates that myeloid cells are essential for promoting new blood vessel formation by secreting various angiogenic factors. Given that hypoxia-inducible factor (HIF) is a critical regulator for angiogenesis, we questioned whether HIF in myeloid cells also plays a role in promoting angiogenesis. To address this question, we generated a unique strain of myeloid-specific knockout mice targeting HIF pathways using human S100A8 as a myeloid-specific promoter. We observed that mutant mice where HIF-1 is transcriptionally activated in myeloid cells (by deletion of the von Hippel-Lindau gene) resulted in erythema, enhanced neovascularization in matrigel plugs, and increased production of vascular endothelial growth factor (VEGF) in the bone marrow, all of which were completely abrogated by either genetic or pharmacological inactivation of HIF-1. We further found that monocytes were the major effector producing VEGF and S100A8 proteins driving neovascularization in matrigel. Moreover, by using a mouse model of hindlimb ischemia we observed significantly improved blood flow in mice intramuscularly injected with HIF-1-activated monocytes. This study therefore demonstrates that HIF-1 activation in myeloid cells promotes angiogenesis through VEGF and S100A8 and that this may become an attractive therapeutic strategy to treat diseases with vascular defects.
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Project description: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.
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Project description:Angiogenesis has been reported participated in temporomandibular joint osteoarthritis (TMJ-OA). While the pathogenesis is unclear, recent studies indicate that hypoxia is important in TMJ-OA. In order to induce osteoarthritis-like lesions in mandibular condyles, rats were sleep deprived experimentally. An increased number of blood vessels were observed in the rats' condyles of SD and SR group compared with controls. Protein and mRNA levels of related factors including VEGF, HIF-1 and Notch were investigated by means of immunohistochemical staining, western blot and real-time PCR, which were highly expressed in the TMJ-OA rats. Furthermore, Cell test was designed to study effects of hypoxia on condylar chondrocytes. We found the expression of VEGF, HIF-1 and Notch were significantly increased in hypoxia group, indicating that HIF-1-Notch-VEGF signaling pathway were activated by hypoxia. The inhibitors of HIF-1 and Notch could suppress the expression of HIF-1, VEGF, Notch, suggesting the HIF-1-VEGF-Notch signaling pathway were bidirectional. Together, hypoxia played an important role in TMJ-OA and accelerates angiogenesis of condylar cartilage through HIF-1-VEGF-Notch signaling pathway. HIF-1? and Notch might be novel therapeutic targets in TMJ-OA.
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Project description:Hypoxia is a hallmark of solid tumours and a key physiological feature distinguishing cancer from normal tissue. However, a major challenge remains in identifying tractable molecular targets that hypoxic cancer cells depend on for survival. Here, we used SILAC-based proteomics to identify the orphan G protein-coupled receptor GPRC5A as a novel hypoxia-induced protein that functions to protect cancer cells from apoptosis during oxygen deprivation. Using genetic approaches in vitro and in vivo, we reveal HIFs as direct activators of GPRC5A transcription. Furthermore, we find that GPRC5A is upregulated in the colonic epithelium of patients with mesenteric ischaemia, and in colorectal cancers high GPRC5A correlates with hypoxia gene signatures and poor clinical outcomes. Mechanistically, we show that GPRC5A enables hypoxic cell survival by activating the Hippo pathway effector YAP and its anti-apoptotic target gene BCL2L1 Importantly, we show that the apoptosis induced by GPRC5A depletion in hypoxia can be rescued by constitutively active YAP. Our study identifies a novel HIF-GPRC5A-YAP axis as a critical mediator of the hypoxia-induced adaptive response and a potential target for cancer therapy.
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Project description:MicroRNAs (miRNAs) are a class of 20-24 nt non-coding RNAs that regulate gene expression primarily through post-transcriptional repression or mRNA degradation in a sequence-specific manner. The roles of miRNAs are just beginning to be understood, but the study of miRNA function has been limited by poor understanding of the general principles of gene regulation by miRNAs. Here we used CNE cells from a human nasopharyngeal carcinoma cell line as a cellular system to investigate miRNA-directed regulation of VEGF and other angiogenic factors under hypoxia, and to explore the principles of gene regulation by miRNAs. Through computational analysis, 96 miRNAs were predicted as putative regulators of VEGF. But when we analyzed the miRNA expression profile of CNE and four other VEGF-expressing cell lines, we found that only some of these miRNAs could be involved in VEGF regulation, and that VEGF may be regulated by different miRNAs that were differentially chosen from 96 putative regulatory miRNAs of VEGF in different cells. Some of these miRNAs also co-regulate other angiogenic factors (differential regulation and co-regulation principle). We also found that VEGF was regulated by multiple miRNAs using different combinations, including both coordinate and competitive interactions. The coordinate principle states that miRNAs with independent binding sites in a gene can produce coordinate action to increase the repressive effect of miRNAs on this gene. By contrast, the competitive principle states when multiple miRNAs compete with each other for a common binding site, or when a functional miRNA competes with a false positive miRNA for the same binding site, the repressive effects of miRNAs may be decreased. Through the competitive principle, false positive miRNAs, which cannot directly repress gene expression, can sometimes play a role in miRNA-mediated gene regulation. The competitive principle, differential regulation, multi-miRNA binding sites, and false positive miRNAs might be useful strategies in the avoidance of unwanted cross-action among genes targeted by miRNAs with multiple targets.
| S-EPMC1762435 | biostudies-literature
Project description:Background and purposeNeovascularization occurring in atherosclerotic lesions may promote plaque expansion, intraplaque haemorrhage and rupture. Oxidized LDL (oxLDL) are atherogenic, but their angiogenic effect is controversial; both angiogenic and anti-angiogenic effects have been reported. The angiogenic mechanism of oxLDL is partly understood, but the role of the angiogenic sphingolipid, sphingosine 1-phosphate (S1P), in this process is not known. Thus, we investigated whether S1P is involved in the oxLDL-induced angiogenesis and whether an anti-S1P monoclonal antibody can prevent this effect.Experimental approachAngiogenesis was assessed by capillary tube formation by human microvascular endothelial cells (HMEC-1) cultured on Matrigel and in vivo by the Matrigel plug assay in C57BL/6 mice.Key resultsHuman oxLDL exhibited a biphasic angiogenic effect on HMEC-1; low concentrations were angiogenic, higher concentrations were cytotoxic. The angiogenic response to oxLDL was blocked by the sphingosine kinase (SPHK) inhibitor, dimethylsphingosine, by SPHK1-siRNA and by an anti-S1P monoclonal antibody. Moreover, inhibition of oxLDL uptake and subsequent redox signalling by anti-CD36 and anti-LOX-1 receptor antibodies and by N-acetylcysteine, respectively, blocked SPHK1 activation and tube formation. In vivo, in the Matrigel plug assay, low concentrations of human oxLDL or murine oxVLDL also triggered angiogenesis, which was prevented by i.p. injection of the anti-S1P antibody.Conclusion and implicationsThese data highlight the role of S1P in angiogenesis induced by oxLDL both in HMEC-1 cultured on Matrigel and in vivo in the Matrigel plug model in mice, and demonstrate that the anti-S1P antibody effectively blocks the angiogenic effect of oxLDL.
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Project description:Hypoxia is a hallmark of solid tumours and a key physiological feature distinguishing cancer from normal tissue. However, a major challenge remains in identifying tractable molecular targets that hypoxic cancer cells depend on for survival. Here, we used SILAC-based proteomics to identify the orphan G-protein-coupled receptor GPRC5A as a novel hypoxia-induced protein that functions to protect cancer cells from apoptosis during oxygen deprivation. Using genetic approaches in vitro and in vivo, we reveal HIFs as direct activators of GPRC5A transcription. Furthermore, we find that GPRC5A is upregulated in the colonic epithelium of patients with mesenteric ischaemia, and in colorectal cancers high GPRC5A correlates with hypoxia gene signatures and poor clinical outcomes. Mechanistically, we show that GPRC5A enables hypoxic cell survival by activating the Hippo pathway effector YAP and its anti-apoptotic target gene BCL2L1. Importantly, we show that the apoptosis induced by GPRC5A depletion in hypoxia can be rescued by constitutively active YAP. Our study identifies a novel HIF-GPRC5A-YAP axis as a critical mediator of the hypoxia-induced adaptive response and a potential target for cancer therapy.
| S-SCDT-EMM-2017-08699 | biostudies-other
Project description:Cocaine induces vasoconstriction in cerebral vessels, which with repeated use can result in transient ischemic attacks and cerebral strokes. However, the neuroadaptations that follow cocaine's vasoconstricting effects are not well understood. Here, we investigated the effects of chronic cocaine exposure (2 and 4 weeks) on markers of vascular function and morphology in the rat brain. For this purpose we measured nitric oxide (NO) concentration in plasma, brain neuronal nitric oxide synthase (nNOS or NOS1), HIF-1α, and VEGF expression in different brain regions, i.e., middle prefrontal cortex, somatosensory cortex, nucleus accumbens, and dorsal striatum, using ELISA or Western blot. Additionally, microvascular density in these brain regions was measured using immunofluorescence microscopy. We showed that chronic cocaine significantly affected NOS1, HIF-1α and VEGF expression, in a region- and cocaine treatment-time- dependent manner. Cerebral microvascular density increased significantly in parallel to these neurochemical changes. Furthermore, significant correlations were detected between VEGF expression and microvascular density in cortical regions (middle prefrontal cortex and somatosensory cortex), but not in striatal regions (nucleus accumbens and dorsal striatum). These results suggest that following chronic cocaine use, as cerebral ischemia developed, NOS1, the regulatory protein to counteract blood vessel constriction, was upregulated; meanwhile, the HIF-VEGF pathway was activated to increase microvascular density (i.e., angiogenesis) and thus restore local blood flow and oxygen supply. These physiological responses were triggered presumably as an adaptation to minimize ischemic injury caused by cocaine. Therefore, effectively promoting such physiological responses may provide novel and effective therapeutic solutions to treat cocaine-induced cerebral ischemia and stroke.
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Project description:Exposure to high altitude environment leads to skeletal muscle atrophy. As a hormone secreted by skeletal muscles after exercise, irisin contributes to promoting muscle regeneration and ameliorating skeletal muscle atrophy, but its role in hypoxia-induced skeletal muscle atrophy is still unclear. Our results showed that 4 w of hypoxia exposure significantly reduced body weight and gastrocnemius muscle mass of mice, as well as grip strength and the duration time of treadmill exercise. Hypoxic treatment increased HIF-1α expression and decreased both the circulation level of irisin and its precursor protein FNDC5 expression in skeletal muscle. In in vitro, CoCl2-induced chemical hypoxia and 1% O2 ambient hypoxia both reduced FNDC5, along with the increase in HIF-1α. Moreover, the decline in the area and diameter of myotubes caused by hypoxia were rescued by inhibiting HIF-1α via YC-1. Collectively, our research indicated that FNDC5/irisin was negatively regulated by HIF-1α and could participate in the regulation of muscle atrophy caused by hypoxia.
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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.
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