C/EBP Homologous Protein-10 (CHOP-10) Limits Postnatal Neovascularization Through Control of Endothelial Nitric Oxide Synthase Gene Expression

Authors:
  • YZYasmine Zouggari
    Yasmine Zouggari
  • BRBhama Ramkhelawon
    Bhama Ramkhelawon
  • CCClément Cochain
    Clément Cochain
  • JVJosé Vilar
    José Vilar
  • ARAdéle Richart
    Adéle Richart
  • DCDominique Charue
    Dominique Charue
  • MDMicheline Duriez
    Micheline Duriez
  • MMMasataka Mori
    Masataka Mori
  • FAFernando Arenzana-Seisdedos
    Fernando Arenzana-Seisdedos
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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.

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