title: C/EBP homologous protein-10 (CHOP-10) limits postnatal neovascularization through control of endothelial nitric oxide synthase gene expression.
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.
  
  
  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.
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK.
authors.forename: Céline
authors.initials: C
authors.lastname: Loinard
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Zouggari
authors.forename: Patricia
authors.initials: P
authors.lastname: Rueda
authors.forename: Bhama
authors.initials: B
authors.lastname: Ramkhelawon
authors.forename: Clément
authors.initials: C
authors.lastname: Cochain
authors.forename: José
authors.initials: J
authors.lastname: Vilar
authors.forename: Alice
authors.initials: A
authors.lastname: Récalde
authors.forename: Adéle
authors.initials: A
authors.lastname: Richart
authors.forename: Dominique
authors.initials: D
authors.lastname: Charue
authors.forename: Micheline
authors.initials: M
authors.lastname: Duriez
authors.forename: Masataka
authors.initials: M
authors.lastname: Mori
authors.forename: Fernando
authors.initials: F
authors.lastname: Arenzana-Seisdedos
authors.forename: Bernard I
authors.initials: BI
authors.lastname: Lévy
authors.forename: Christophe
authors.initials: C
authors.lastname: Heymes
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Silvestre
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000201:enzymology / Q000235:genetics; D005263:Femoral Artery / Q000201:enzymology / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis / Q000235:genetics*; D011485:Protein Binding / Q000235:genetics; D051742:Transcription Factor CHOP / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: C497250:Ddit3 protein, mouse; D051742:Transcription Factor CHOP; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse