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

Urbich, Carmen; Rössig, Lothar; Kaluza, David; Potente, Michael; Boeckel, Jes Niels; Knau, Andrea; Diehl, Florian; Geng, Jian Guo; Hofmann, Wolf Karsten; Zeiher, Andreas M.; Dimmeler, Stefanie

doi:10.1182/blood-2009-01-196485

Cited by 146 publications

(139 citation statements)

References 53 publications

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“…Previous studies have identified HDAC5 as a negative regulator of angiogenesis and HDAC7 as a positive regulator of angiogenesis (Chang et al, 2006;Urbich et al, 2009). Interestingly, both HDAC5 and HDAC7 undergo active nucleocytoplasmic shuttling in response to extracellular signals (McKinsey et al, 2000;Vega et al, 2004), which may allow for fine-tuning of angiogenesis-related genes.…”

Section: Discussionmentioning

confidence: 99%

Microtubule-associated deacetylase HDAC6 promotes angiogenesis by regulating cell migration in an EB1-dependent manner

Xie

Ren

et al. 2011

Protein Cell

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Angiogenesis, a process by which the preexisting blood vasculature gives rise to new capillary vessels, is associated with a variety of physiologic and pathologic conditions. However, the molecular mechanism underlying this important process remains poorly understood. Here we show that histone deacetylase 6 (HDAC6), a microtubule-associated enzyme critical for cell motility, contributes to angiogenesis by regulating the polarization and migration of vascular endothelial cells. Inhibition of HDAC6 activity impairs the formation of new blood vessels in chick embryos and in angioreactors implanted in mice. The requirement for HDAC6 in angiogenesis is corroborated in vitro by analysis of endothelial tube formation and capillary sprouting. Our data further show that HDAC6 stimulates membrane ruffling at the leading edge to promote cell polarization. In addition, microtubule end binding protein 1 (EB1) is important for HDAC6 to exert its activity towards the migration of endothelial cells and generation of capillary-like structures. These results thus identify HDAC6 as a novel player in the angiogenic process and offer novel insights into the molecular mechanism governing endothelial cell migration and angiogenesis.

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Section: Discussionmentioning

confidence: 99%

Microtubule-associated deacetylase HDAC6 promotes angiogenesis by regulating cell migration in an EB1-dependent manner

Xie

Ren

et al. 2011

Protein Cell

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“…HDAC5 has been shown to act as a signal-responsive repressor of cardiac hypertrophy, skeletal muscle differentiation and bone development (McKinsey et al 2000, Zhang et al 2002, Vega et al 2004a. There are numerous target genes regulated by HDAC5, among which bFGF was discovered and also the transcriptome of cells transfected with HDAC5 siRNA was profiled by Urbich et al (2009). Among the significantly regulated genes with altered RNA levels are the genes involved in angiogenesis, including angiogenic growth factors and receptors (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…By binding to the promoter of the bFGF (FGF2) and SLIT2 genes, HDAC5 represses the expression of these pro-angiogenic genes, whereas HDAC5 silencing promotes capillary sprouting of endothelial cells (Urbich et al 2009). Accordingly, we propose that a new signaling pathway of integrin avb3/PKD/HDAC5 is involved in regulating bFGF expression, which further affects the angiogenesis induced by thyroid hormone.…”

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confidence: 98%

Thyroid hormone induced angiogenesis through the integrin αvβ3/protein kinase D/histone deacetylase 5 signaling pathway

Liu¹,

Zheng²,

Shi³

et al. 2014

Journal of Molecular Endocrinology

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Thyroid hormone is reported to induce angiogenesis, which is mediated by the membrane receptor integrin avb3, but the precise signaling pathway is still not very clear. Recently, studies have shown that protein kinase D (PKD) regulates the recycling of integrin avb3, which is required for cell migration. Moreover, phosphorylated PKD stimulates histone deacetylase 5 (HDAC5) phosphorylation and nuclear export in endothelial cells. As a potent pro-angiogenic growth factor, basic fibroblast growth factor (bFGF (FGF2)) is a downstream target gene of HDAC5. Therefore, we examined the hypothesis that a novel signaling pathway through integrin avb3/PKD/HDAC5 might contribute to thyroxine (T 4 )-induced angiogenesis. We selected human umbilical vein endothelial cells (HUVECs) for treatment. Angiogenesis was assessed using wound-healing and tubulogenesis assays. Signaling molecules, including phosphorylated PKD and HDAC5, were measured by western blotting. bFGF mRNA was analyzed by real-time PCR. Our results showed that T 4 (100 nmol/l) stimulated the migration and formation of tube-like structures of HUVECs, whereas tetraiodothyroacetic acid (Tetrac, 100 nmol/l) inhibited T 4 -induced cell migration. Importantly, T 4 promoted the phosphorylation of PKD and HDAC5. These effects were inhibited respectively by Tetrac, PKC inhibitor (2.5 mmol/l) and PKD siRNA. Meanwhile, T 4 could promote the cytoplasmic accumulation of phosphorylated HDAC5 in HUVECs. In addition, bFGF mRNA expression in HUVECs significantly increased within 2 h of T 4 treatment, but was decreased by Tetrac. Our findings indicate that T 4 increases the expression of bFGF mRNA via the integrin avb3/PKD/HDAC5 signaling pathway, which plays an important role in angiogenesis.

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“…After treatment with or without HA for 1 h, cells were treated as indicated and then fixed as described previously (Urbich et al, 2009). Cover slips were incubated with a primary antibody to pERK (Santa Cruz: 1/500 dilution) or RHAMM (Santa Cruz: 1/500 dilution) at 4°C for 24 h. After washing with PBS, slides were incubated with Alexa Fluor 488 (for RHAMM) or Alexa Fluor 568 (for pERK)-conjugated secondary antibody for 1 h. After washing and mounting, fluorescence staining was visualized using confocal microscopy.…”

Section: Immunofluorescence Stainingmentioning

confidence: 99%

Hyaluronic Acid Promotes Angiogenesis by Inducing RHAMM-TGFβ Receptor Interaction via CD44-PKCδ

Park

Kim

et al. 2012

Molecules and Cells

146

101

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

Cited by 146 publications

References 53 publications

Microtubule-associated deacetylase HDAC6 promotes angiogenesis by regulating cell migration in an EB1-dependent manner

Microtubule-associated deacetylase HDAC6 promotes angiogenesis by regulating cell migration in an EB1-dependent manner

Thyroid hormone induced angiogenesis through the integrin αvβ3/protein kinase D/histone deacetylase 5 signaling pathway

Hyaluronic Acid Promotes Angiogenesis by Inducing RHAMM-TGFβ Receptor Interaction via CD44-PKCδ

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