Histone deacetylase 9 promotes angiogenesis by targeting the antiangiogenic MicroRNA-17-92 cluster in endothelial cells

David Kaluza, Jens Kroll, Sabine Gesierich, Yosif Manavski, Jes Niels Boeckel, Carmen Doebele, Arthur Zelent, Lothar Rössig, Andreas M. Zeiher, Hellmut G. Augustin, Carmen Urbich, Stefanie Dimmeler

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

Objective-Histone deacetylases (HDACs) modulate gene expression by deacetylation of histone and nonhistone proteins. Several HDACs control angiogenesis, but the role of HDAC9 is unclear. Methods and Results-Here, we analyzed the function of HDAC9 in angiogenesis and its involvement in regulating microRNAs. In vitro, silencing of HDAC9 reduces endothelial cell tube formation and sprouting. Furthermore, HDAC9 silencing decreases vessel formation in a spheroid-based Matrigel plug assay in mice and disturbs vascular patterning in zebrafish embryos. Genetic deletion of HDAC9 reduces retinal vessel outgrowth and impairs blood flow recovery after hindlimb ischemia. Consistently, overexpression of HDAC9 increases endothelial cell sprouting, whereas mutant constructs lacking the catalytic domain, the nuclear localization sequence, or sumoylation site show no effect. To determine the mechanism underlying the proangiogenic effect of HDAC9, we measured the expression of the microRNA (miR)-17-92 cluster, which is known for its antiangiogenic activity. We demonstrate that silencing of HDAC9 in endothelial cells increases the expression of miR-17-92. Inhibition of miR-17-20a rescues the sprouting defects induced by HDAC9 silencing in vitro and blocking miR-17 expression partially reverses the disturbed vascular patterning of HDAC9 knockdown in zebrafish embryos. Conclusion-We found that HDAC9 promotes angiogenesis and transcriptionally represses the miR-17-92 cluster.

Original languageEnglish (US)
Pages (from-to)533-543
Number of pages11
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume33
Issue number3
DOIs
StatePublished - Mar 1 2013

Keywords

  • angiogenesis
  • histone deacetylase 9 and histone deacetylase 5
  • histone deacetylases
  • miR-17
  • microRNAs

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Kaluza, D., Kroll, J., Gesierich, S., Manavski, Y., Boeckel, J. N., Doebele, C., Zelent, A., Rössig, L., Zeiher, A. M., Augustin, H. G., Urbich, C., & Dimmeler, S. (2013). Histone deacetylase 9 promotes angiogenesis by targeting the antiangiogenic MicroRNA-17-92 cluster in endothelial cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 33(3), 533-543. https://doi.org/10.1161/ATVBAHA.112.300415