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HDAC5 is a repressor of angiogenesis and determines the angiogenic gene expression pattern of endothelial cells

ABSTRACT: Class IIa histone deacetylases (HDACs) are signal-responsive regulators of gene expression involved in vascular homeostasis. To investigate the differential role of class IIa HDACs for the regulation of angiogenesis, we used siRNA to specifically suppress the individual HDAC isoenzymes. Among the HDAC isoforms tested, silencing of HDAC5 exhibited a unique pro-angiogenic effect evidenced by increased endothelial cell migration, sprouting and tube formation. Consistently, overexpression of HDAC5 decreased sprout formation, indicating that HDAC5 is a negative regulator of angiogenesis. The anti-angiogenic activity of HDAC5 was independent of MEF2 binding and its deacetylase activity, but required a nuclear localization indicating that HDAC5 might affect the transcriptional regulation of gene expression. To identify putative HDAC5 targets, we performed microarray expression analysis. Silencing of HDAC5 increased the expression of fibroblast growth factor 2 (FGF2) and angiogenic guidance factors including Slit2. Antagonization of FGF2 or Slit2 reduced sprout induction in response to HDAC5 siRNA. ChIP assays demonstrate that HDAC5 binds to the promoter of FGF2 and Slit2. In summary, HDAC5 represses angiogenic genes, like FGF2 and Slit2, which causally contribute to capillary-like sprouting of endothelial cells. The de-repression of angiogenic genes by HDAC5 inactivation may provide a useful therapeutic target for induction of angiogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE15499 | GEO | 2009/04/02

SECONDARY ACCESSION(S): PRJNA115663

REPOSITORIES: GEO

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RNAi of human HUVEC cells knocked down for HDAC isoenzymes reveals sHDAC5 is a repressor of angiogenesis and determines the angiogenic gene expression pattern of endothelial cells

Project description:Class IIa histone deacetylases (HDACs) are signal-responsive regulators of gene expression involved in vascular homeostasis. To investigate the differential role of class IIa HDACs for the regulation of angiogenesis, we used siRNA to specifically suppress the individual HDAC isoenzymes. Among the HDAC isoforms tested, silencing of HDAC5 exhibited a unique pro-angiogenic effect evidenced by increased endothelial cell migration, sprouting and tube formation. Consistently, overexpression of HDAC5 decreased sprout formation, indicating that HDAC5 is a negative regulator of angiogenesis. The anti-angiogenic activity of HDAC5 was independent of MEF2 binding and its deacetylase activity, but required a nuclear localization indicating that HDAC5 might affect the transcriptional regulation of gene expression. To identify putative HDAC5 targets, we performed microarray expression analysis. Silencing of HDAC5 increased the expression of fibroblast growth factor 2 (FGF2) and angiogenic guidance factors including Slit2. Antagonization of FGF2 or Slit2 reduced sprout induction in response to HDAC5 siRNA. ChIP assays demonstrate that HDAC5 binds to the promoter of FGF2 and Slit2. In summary, HDAC5 represses angiogenic genes, like FGF2 and Slit2, which causally contribute to capillary-like sprouting of endothelial cells. The de-repression of angiogenic genes by HDAC5 inactivation may provide a useful therapeutic target for induction of angiogenesis. Experiment Overall Design: 6 samples: 3x siSCRAMBLED transfected HUVEC (control) + 3x siHDAC5 transfected HUVEC 24h after transfection

2009-04-11 | E-GEOD-15499 | biostudies-arrayexpress

Slit2 modifies VEGF-induced angiogenic responses in rabbit skeletal muscle by inducing capillary sprouting and decreasing vascular permeability via reduced eNOS activity

Project description:Rationale: Slit2 is a possible modulator of vascular endothelial growth factor (VEGF) - induced angiogenesis, but its effects have not been tested in large animal models. Objective: We studied the effect of Slit2 on therapeutic angiogenesis induced by VEGF receptor 2 (VEGFR2) ligands Vammin and VEGF-DΔNΔC in vivo in rabbit skeletal muscles. The Slit2 target genes were also studied by RNA sequencing (RNA-Seq) in endothelial cells. Methods and Results: Adenoviral intramuscular gene transfers were performed into rabbit hindlimbs. Confocal and multiphoton microscopy were used for blood vessel imaging. Signaling experiments and gene expression analyses were performed to study mechanisms of Slit2 action. Slit2 decreased VEGFR2-mediated vascular permeability. It also reduced VEGFR2-mediated increase in blood perfusion and capillary enlargement, whereas sprouting of the capillaries was increased. Slit2 gene transfer alone did not have any effects on vascular functions or morphology. VEGFR2 activation was not affected by Slit2, but eNOS phosphorylation was diminished. The transcriptome profiling showed Slit2 downregulating angiogenesis-related genes such as nuclear receptor subfamily 4 group A member 1 (NR4A1) and Stanniocalcin-1 (STC-1) as well as genes related to endothelial cell migration and vascular permeability. Conclusions: Combining Slit2 with VEGFs adjusts VEGFR2-mediated angiogenic effects into a more physiological direction. This possibly allows the use of higher VEGF vector doses to achieve a more widespread vector and VEGF distribution in the target tissues leading to a better therapeutic outcome while reducing excess vascular permeability. HUVEC mRNA profiles after adenoviral vector gene transfers in duplicate.

2015-05-26 | E-GEOD-63283 | biostudies-arrayexpress

HDAC5 loss in pancreatic cancer induces enhanced arachidonic acid metabolism via overactivated GATA1-cPLA2 axis

Project description:Unlike class I Histone deacetylase (HDAC) members (HDAC1, 2, 3, etc.), HDAC5, a class IIa HDAC member, is downregulated in multiple solid tumors, including pancreatic cancer, and its loss is associated with unfavorable prognosis. Additionally, HDAC5’s expression correlates negatively with arachidonic acid (AA) metabolism, which is highly implicated in inflammatory responses and cancer progression. This study aimed to elucidate the role of HDAC5 in AA metabolism and its prospect in the treatment of pancreatic cancer.

2023-08-01 | GSE207863 | GEO

Slit2 modifies VEGF-induced angiogenic responses in rabbit skeletal muscle by inducing capillary sprouting and decreasing vascular permeability via reduced eNOS activity

2015-05-26 | GSE63283 | GEO

Impairment of human terminal erythroid differentiation by histone deacetylase 5 deficiency

Project description:Histone deacetylases (HDACs) are a group of enzymes catalyzing the removal of acetyl groups from histone and non-histone proteins. HDACs have been shown to play diverse functions in a wide range of biological processes. However, their roles in mammalian erythropoiesis remain to be fully defined. We show here that of the eleven classic HDAC family members, six of them (HDAC 1,2,3 and HDAC 5,6,7) are expressed in human erythroid cells with HDAC5 significantly up regulated during terminal erythroid differentiation. Knockdown of HDAC5 in human CD34+ cells followed by erythroid cell culture led to increased apoptosis, decreased chromatin condensation, and impaired enucleation of erythroblasts.

2021-06-01 | GSE151743 | GEO

Gene regulation in gastrocnemius muscle of denervated mouse with HDAC4 inducible knockout or class IIa HDAC inhibitior NVS-HD1 treatment

Project description:Our class IIa HDAC inhibitor, NVS-HD1, inhibited HDAC4 with less than 1 nM potency while exhibiting >200 fold selectivity on class IIa HDACs compared to class I (HDAC1, 3, 8) and class IIb (HDAC6) HDACs, making it the most potent and selective class IIa HDAC inhibitor reported so far. We tested the efficacy of NVS-HD1 in the mouse denervation model, either alone or on the genetic background of HDAC4 whole-body inducible knockout (HDAC4 iRKO). Global gene expression changes in gastrocnemius muscles were profiled by RNAseq. In the innervated control legs, HDAC4 knockout or NVS-HD1 caused little changes in gene expression compared to WT mice. HDAC4 knockout or NVS-HD1 mainly reversed denervation induced changes and the genes regulated by them largely overlap, suggesting that NVS-HD1 is quite specific against class IIa HDACs.

2019-11-27 | GSE136627 | GEO

Transcriptome profiling of human urothelial carcinoma cell lines RT-112, VM-Cub-1, SW1710, UMUC3 and a benign urothelial control HBLAK engineered to stably express HDAC5 against their vector control

Project description:Aberrant expression of histone deacetylases (HDACs) and their activity are associated with a broad range of tumor development. However, based on cell or tissue types, class IIA HDACs such as HDAC4 and HDAC5 may facilitate or inhibit cancer progression. The goal of this project is to examine the gene expression changes caused by HDAC5 expression. Here, we studied the effects of stable expression of HDAC5 (that is normally downregulated or have a weak basal expression) in four urothelial carcinoma (UC) cell lines (RT112, VM-Cub-1, SW1710, and UM-UC-3) by rRNA-depleted RNA-sequencing in comparison to their vector controls. We observed that HDAC5 expression in VM-Cub-1 triggered a drastic phenotype change from an epitheloid to a mesenchymal (i.e., epithelial-mesenchymal transition, EMT) and altogether diminished cell proliferation of the other three cell lines. Our RNA-seq data are in line with the phenotypic transformation of VM-Cub-1. In addition, we also performed a gene expression profiling of HBLAK, a spontaneously immortalized from primary human bladder epithelial cells that can be directly compared with the four UC vector cells. HBLAK vector cells only were included for RNA-seq as the cells failed to express HDAC5 after lentiviral transduction and selection.

2019-11-13 | E-MTAB-8418 | biostudies-arrayexpress

Differential gene expression analysis of 4days post fertilization (dpf) wildtype and flt1ka601zebrafish mutants to identify venous sprouting associated genes

Project description:Formation of organ-specific vasculatures requires cross-talk between developing tissue and specialized endothelial cells. Here we show how developing zebrafish spinal cord neurons coordinate vessel growth through balancing of neuron-derived Vegfaa, with neuronal sFlt1 restricting Vegfaa-Kdrl mediated angiogenesis at the neurovascular interface. Neuron-specific loss of flt1 or increased neuronal vegfaa expression promotes angiogenesis and peri-neural tube vascular network formation. Combining loss of neuronal flt1 with gain of vegfaa promotes sprout invasion into the neural tube. Upon loss of neuronal flt1, ectopic sprouts emanate from veins involving special angiogenic cell behaviors including nuclear positioning and a molecular signature distinct from primary artery or secondary venous sprouting. Manipulation of AV identity or Notch signaling established that ectopic sprouting in flt1 mutants requires venous endothelium. Conceptually our data suggest that spinal cord vascularization proceeds from veins involving two-tiered regulation of neuronal sFlt1 and Vegfaa via a novel sprouting mode.

2016-11-01 | GSE89350 | GEO

Protein expression profiling of human urothelial carcinoma cell lines RT-112, VM-Cub-1, SW1710, UMUC3 and a benign urothelial control HBLAK engineered to stably express HDAC5 against their vector control

Project description:Aberrant expression of histone deacetylases (HDACs) and their activity are associated with a broad range of tumor development. However, based on cell or tissue types, class IIA HDACs such as HDAC4 and HDAC5 may facilitate or inhibit cancer progression. The goal of this project is to examine the overall proteome changes caused by HDAC5 expression. Here, we studied the effects of stable expression of HDAC5 (that is normally downregulated or have a weak basal expression) in four urothelial carcinoma (UC) cell lines (RT112, VM-Cub-1, SW1710, and UM-UC-3) by mass spectrometry in comparison to their vector controls. We observed that HDAC5 expression in VM-Cub-1 triggered a drastic phenotype change from an epitheloid to a mesenchymal (i.e., epithelial-mesenchymal transition, EMT) and altogether diminished cell proliferation of the other three cell lines. Our mass-spec data are in line with the phenotypic transformation of VM-Cub-1. In addition, we also performed a protein expression profiling of HBLAK, a spontaneously immortalized from primary human bladder epithelial cells that can be directly compared with the four UC vector cells. HBLAK vector cells only were included for mass-spec as the cells failed to express HDAC5 after lentiviral transduction and selection.

2022-03-14 | PXD014448 | Pride

KSHV vIRF3 promotes angiogenesis of lymphatic endothelial cells (LECs)

Project description:Herein, we report viral interferon regulatory factor 3 (vIRF3) as a pro-angiogenic factor together with HDAC5 that coordinates with LEC transcriptome, thus resulting in hyper-sprouting formation and ultimately leading to abnormal lymphangiogenesis. Overexpression of vIRF3 in LECs but not blood endothelial cells (BECs) exhibited a unique KSHV-associated angiogenic effect, evidenced by elongated spindle shape, sprouting, and tube formation. Furthermore, using vIRF3 knockout recombinant KSHV, we confirmed that vIRF3 is a critical factor of KSHV-mediated lymphangiogenesis in primary LECs.

2017-12-19 | GSE102132 | GEO

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