C/EBP Homologous Protein-10 (CHOP-10) limits postnatal neovascularization through control of endothelial nitric oxide synthase gene expression

Céline Loinard, Yasmine Zouggari, Patricia Rueda, Bhama Ramkhelawon, Clément Cochain, José Vilar, Alice Récalde, Adéle Richart, Dominique Charue, Micheline Duriez, Masataka Mori, Fernando Arenzana-Seisdedos, Bernard I. Lévy, Christophe Heymes, Jean Sébastien Silvestre

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Abstract

BACKGROUND - C/EBP homologous protein-10 (CHOP-10) is a novel developmentally regulated nuclear protein that emerges as a critical transcriptional integrator among pathways regulating differentiation, proliferation, and survival. In the present study, we analyzed the role of CHOP-10 in postnatal neovascularization. METHODS AND RESULTS - Ischemia was induced by right femoral artery ligation in wild-type and CHOP-10 mice. In capillary structure of skeletal muscle, CHOP-10 mRNA and protein levels were upregulated by ischemia and diabetes mellitus. Angiographic score, capillary density, and foot perfusion were increased in CHOP-10 mice compared with wild-type mice. This effect was associated with a reduction in apoptosis and an upregulation of endothelial nitric oxide synthase (eNOS) levels in ischemic legs of CHOP-10 mice compared with wild-type mice. In agreement with these results, eNOS mRNA and protein levels were significantly upregulated in CHOP-10 short interfering RNA-transfected human endothelial cells, whereas overexpression of CHOP-10 inhibited basal transcriptional activation of the eNOS promoter. Using a chromatin immunoprecipitation assay, we also showed that CHOP-10 was bound to the eNOS promoter. Interestingly, enhanced postischemic neovascularization in CHOP-10 mice was fully blunted in CHOP-10/eNOS double-knockout animals. Finally, we showed that induction of diabetes mellitus is associated with a marked upregulation of CHOP-10 that substantially inhibited postischemic neovascularization. CONCLUSIONS - This study identifies CHOP-10 as an important transcription factor modulating vessel formation and maturation.

Original languageEnglish
Pages (from-to)1014-1026
Number of pages13
JournalCirculation
Volume125
Issue number8
DOIs
Publication statusPublished - 28 Feb 2012
Externally publishedYes

Keywords

  • angiogenesis
  • CHOP-10
  • diabetes
  • eNOS
  • ischemia
  • vasculogenesis

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