EZH2 modulates angiogenesis in vitro and in a mouse model of limb ischemia

Tijana Mitić, Andrea Caporali, Ilaria Floris, Marco Meloni, Micol Marchetti, Raul Urrutia, Gianni D. Angelini, Costanza Emanueli

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Epigenetic mechanisms may regulate the expression of pro-angiogenic genes, thus affecting reparative angiogenesis in ischemic limbs. The enhancer of zest homolog-2 (EZH2) induces thtrimethylation of lysine 27 on histone H3 (H3K27me3), which represses gene transcription. We explored (i) if EZH2 expression is regulated by hypoxia and ischemia; (ii) the impact of EZH2 on the expression of two pro-angiogenic genes: eNOS and BDNF; (iii) the functional effect of EZH2 inhibition on cultured endothelial cells (ECs); (iv) the therapeutic potential of EZH2 inhibition in a mouse model of limb ischemia (LI). EZH2 expression was increased in cultured ECs exposed to hypoxia (control: normoxia) and in ECs extracted from mouse ischemic limb muscles (control: absence of ischemia). EZH2 increased the H3K27me3 abundance onto regulatory regions of eNOS and BDNF promoters. In vitro RNA silencing or pharmacological inhibition by 3-deazaneplanocin (DZNep) of EZH2 increased eNOS and BDNF mRNA and protein levels and enhanced functional capacities (migration, angiogenesis) of ECs under either normoxia or hypoxia. In mice with experimentally induced LI, DZNep increased angiogenesis in ischaemic muscles, the circulating levels of pro-angiogenic hematopoietic cells and blood flow recovery. Targeting EZH2 for inhibition may open new therapeutic avenues for patients with limb ischemia.

Original languageEnglish (US)
Pages (from-to)32-42
Number of pages11
JournalMolecular Therapy
Volume23
Issue number1
DOIs
StatePublished - Jan 10 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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    Mitić, T., Caporali, A., Floris, I., Meloni, M., Marchetti, M., Urrutia, R., Angelini, G. D., & Emanueli, C. (2015). EZH2 modulates angiogenesis in vitro and in a mouse model of limb ischemia. Molecular Therapy, 23(1), 32-42. https://doi.org/10.1038/mt.2014.163