Relief of hypoxia by angiogenesis promotes neural stem cell differentiation by targeting glycolysis
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PROVIDER: PRJEB11184 | ENA |
REPOSITORIES: ENA
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Project description:The neural stem cell (NSC) niche controls the expansion and differentiation of NSCs. Blood vessels are part of this neurogenic niche, but their functional significance for the regulation of NSC differentiation and the mechanisms involved remain unclear. Here, we report that blood vessel formation in the developing mouse and ferret cortex coincided with induction of NSC differentiation in time and space. Moreover, selective inhibition of brain angiogenesis in vessel-specific Gpr124 null embryos caused hypoxia and increased NSC expansion at the expense of differentiation. The hypoxia-inducible factor (HIF)-1Îą mediated this process, as the level of HIF-1Îą controlled NSC differentiation. Niche blood vessels regulated NSC differentiation at least in part by providing oxygen, as exposure to increased ambient oxygen levels rescued NSC differentiation in hypoxic brains of Gpr124 deficient embryos. Our findings establish a novel oxygen-dependent mechanism of how blood vessels regulate NSC differentiation.
2016-02-04 | E-MTAB-3941 | biostudies-arrayexpress
Project description: Not available
| S-EPMC5207321 | biostudies-literature
Project description:Relief of tumor hypoxia unleashes the tumoricidal potential of neutrophils
| PRJNA565424 | ENA
Project description:Oxygen fluctuation during tissue remodeling imposes a major metabolic challenge in human tumors. Stem-like tumor cells in glioblastomas are believed to possess extraordinary metabolic flexibility, enabling them to initiate growth even under non-permissive conditions. To identify adaptive response mechanism, we compared the effects of acute and chronic hypoxia versus oxygenation on stem-like glioblastoma (GS) cells. GS cell lines were established and propagated either under normoxia (21% O2) or hypoxia (1% O2) and subsequently exposed to acute normoxia or hypoxia, respectively. Gene expression profiling revealed that acute hypoxia predominantly induced metabolic pathways and cell cycle arrest, whereas chronic hypoxia activated neurodevelopmental processes. In particular, we found increased expression of glycolytic enzymes, especially of the preparatory phase of glycolysis, under acute hypoxia, whereas pentose phosphate pathway (PPP) enzymes were downregulated. The opposite was found for acute oxygenation of hypoxic GS cells. Findings were confirmed by qPCR and immunoblot analyses. Despite downregulation by hypoxia, expression of PPP enzymes is increased in GBMs compared to normal brain, whereas expression of hypoxia-inducible enzymes of the parallel preparatory phase of glycolysis is decreased. Immunohistochemistry revealed strong staining for PPP enzymes in the bulk of GBM tissue, especially in highly proliferative areas, but not in pseudopalisading (hypoxic) cells. Glycolytic enzymes displayed an inverse pattern. Mass spectrometric analysis using [1,2-13C2]-D-glucose showed reduced glucose flux through the PPP under hypoxia in favor of flux through glycolysis. Acute and chronic hypoxia increased cell migration but reduced proliferation, whereas normoxia had opposite effects. Our findings extend Warburg’s observations by showing that in most tumor cells the PPP, which supplies metabolites for biomass production, is favored over the parallel preparatory phase of glycolysis, but is suppressed under acute severe hypoxia, causing a switch to direct glycolysis to protect against hypoxic stress.
2020-12-31 | GSE45117 | GEO
Project description:Purpose: Jumonji-containing (jmjC) family of proteins are involved in epigenetic gene regulation through histone specific lysine demethylation. Previous studies have demonstrated that the expression of several members of this family is induced by hypoxia. However, the mechanisms by which lysine specific demethylases (KDMs) are regulated under hypoxia and how they affect angiogenesis, the primary method to restore blood oxygen, remains unknown. In this study, we characterized regulation of KDMs using a combination of nascent and mature mRNA profiling. Furthermore, we aimed to identify KDMs that play a role in mediating the VEGF-mediated angiogenic response in endothelial cells. Results: We demonstrated that majority of KDMs were induced by hypoxia and this effect is more prominent upon constitutive activation of HIF2α compared to HIF1α. Half of the changes in mRNAs levels were attributed to transcriptional regulation as evidenced by similar changes at the level of nascent mRNAs, whereas half was likely due to post-transcriptional mechanisms affecting mature mRNA levels. Hypoxia induced genome-wide redistribution of H3K27me3 at 2000 transcriptionally active loci in human umbilical vein endothelial cells (HUVECs). Among these, we further verified the induction of VEGF-A by demethylation of the locus by KDM4B and KDM6B in response to hypoxia. Accordingly, knockdown of KDM4B and KDM6B led to decreased proliferation and tube formation of HUVECs. Conclusions: Hypoxia leads to both transcriptional and post-transcriptional induction of KDMs and wide redistribution of H3K27me3 at active chromatin regions. Main mediator of angiogenesis, VEGFA, is regulated by KDM4B- and KDM6B- mediated demethylation in HUVECs with functional implications for cell proliferation and tube formation. These findings provide novel insights into the regulation of KDMs by hypoxia and the epigenetic regulation of angiogenesis.
2020-09-03 | GSE139678 | GEO
Project description:The Warburg effect, consisting of increased glucose uptake and glycolysis, provides metabolic energy as well as cellular building blocks for tumor growth. Inhibition of the Warburg effect with 2-deoxyglucose (2DG) has been explored in clinical trials with limited efficacy. Blockage of glycolysis can induce autopahgy resulting in alternative energy generation through oxidative phosphorylation providing a potential bypass of the effects of inhibition of glycolysis. Here in we demonstrate that activation of AMPK, as a consequence of energetic stress, induces mitochondrial energy production potentially bypassing the effects of glycolysis inhibition. We thus combined blockage of glycolysis by 2DG with inhibition of the electron transfer complex I (ETC1) in the mitochondria with the clinically applicable antidiabetic drug metformin. The combination resulted in activation of AMPK and autopahgy that however rendered eventual depletion of ATP and cell death. Furthermore, combined inhibition of glycolysis and mitochondrial respiration inhibited tumor growth and markedly decreased metastatic capacity in vivo. In order to understand the mechanism of these metabolic inhibitors, we performed whole genome transcriptional analysis. Human SK-4 esophageal cancer cell lines were treated with 5 different treatment groups [2 deoxy glucose (4mM), Metformin (5mM), AICAR (2mM), 2 deoxy glucose (4mM) plus Metformin (5mM) and 2 deoxy glucose (4mM) plus AICAR (2mM)] with non treated control groups for 12 hrs. Each groups was quadruplicated. Microarray experiments and data analysis were done at Dept. of Systems Biology, MDACC (Houston, USA)
2012-12-31 | E-GEOD-16816 | biostudies-arrayexpress
Project description:Pathologic retinal neovascularization is a potentially blinding consequence seen in many common diseases including diabetic retinopathy, retinopathy of prematurity, and retinal vascular occlusive diseases, among others. The use of therapeutics targeting pro-angiogenesis factors such as vascular endothelial growth factor (VEGF) has proven to be highly effective, however considerable side effects exist and serial anti-VEGF treatment has been shown to decrease effectiveness over time. Characterization of additional regulators of neovascularization is needed to further understand neovascular disease and identify possible new therapeutic targets. This study investigates epithelial membrane protein 2 (EMP2) and its role as a possible modulator of angiogenesis in human retinal pigment epithelium (RPE) under hypoxia. EMP2 is highly expressed in human RPE and RPE cell lines. Adult retinal pigment epithelial cell line-19 (ARPE-19) cells were genetically modified to either overexpress EMP2 (OE) or knock down EMP2 (KD) and expression at the RNA and protein level was evaluated using RNA sequencing and western blot respectively. Protein expression was evaluated under both normoxic conditions and conditions of hypoxic stress with 0.5% O2. EMP2 expression was found to positively correlate with expression of the pro-angiogenesis factors hypoxia inducible factor 1-alpha (HIF-1a) and VEGF for both RNA and protein. EMP2 mediated changes in ARPE-19 cells was also found to alter the secretion of a paracrine factor(s) in conditioned media that can regulate human umbilical vein endothelial cells (HUVEC) endothelial cell migration and capillary tube formation in in vitro functional angiogenesis assays. This study identifies EMP2 as a potentially important mediator of angiogenesis in the human RPE, a tissue involved in abnormal retinal neovascularization in a number of diseases. EMP2 levels positively correlate with those of the potent pro-angiogenesis mediators HIF-1a and VEGF, however the mechanism of this relationship remains to be clarified. This study supports further investigation of EMP2 as a promising novel target for therapeutic treatment of pathologic neovascularization in the retina.
2020-06-03 | GSE151610 | GEO
Project description:Background: Hypoxia can affect aerobic organisms profoundly. Biological responses to extreme hypoxia have been well studied. However, it is not well characterized how living organisms respond to mild hypoxia, and how they distinguish different levels of hypoxia. Results: We examined the transcriptional responses of locusts using microarrays to reveal their strategies to cope with mild hypoxia. Mitochondrial activities were systemically suppressed, mainly involving energy production and mitochondrial biogenesis. The functions of endoplasmic reticulum were activated to clear the dysfunctional proteins and rescue newly synthesized proteins. Glucose in cytosol was shunted from glycolysis to pentose phosphate pathway probably to tackle the oxidative stress by enhancing the production of reductive forces. Conclusions: LocustsM-bM-^@M-^Y responses to mild hypoxia differ from that to severe hypoxia . In severe hypoxia, glucose resources are shunted to glycolysis to produce ATP and tackle energy crisis; however, in mild hypoxia, they are diverted to produce reductive forces and deal with oxidative stress. Locusts are capable of distinguishing different levels of hypoxia and initiating proper defenses. Simulated 4km altitude hypoxia treatment vs. normoxia control;direct comparison on 6 separate microarrays; each microarray compares one biological replicate of treatment and control; each biological replicate contains 10 individuals
2012-12-12 | E-GEOD-33898 | biostudies-arrayexpress
Project description:Hypoxia is an important driver of cancer progression, and rapidly growing tumors often result in intratumoral hypoxic regions. Hypoxia is associated with metabolic reprogramming and angiogenesis, resulting in enhanced tumor progression. Here, we aimed to study breast cancer hypoxia responses at the proteomic level, and we wanted to identify differences in protein secretion from luminal-like and basal-like cell lines before and after hypoxia.
2023-06-23 | PXD027136 | Pride
Project description:Hypoxia-mediated regulation of histone demethylases affects angiogenesis associated functions in endothelial cells
| PRJNA586868 | ENA