title: Correlating global gene regulation to angiogenesis in the developing chick extra-embryonic vascular system.
abstract: BACKGROUND
  Formation of blood vessels requires the concerted regulation of an unknown number of genes in a spatial-, time- and dosage-dependent manner. Determining genes, which drive vascular maturation is crucial for the identification of new therapeutic targets against pathological angiogenesis.
  
  
  RESULTS
  [corrected] We accessed global gene regulation throughout maturation of the chick chorio-allantoic membrane (CAM), a highly vascularized tissue, using pan genomic microarrays. Seven percent of analyzed genes showed a significant change in expression (>2-fold, FDR<5%) with a peak occurring from E7 to E10, when key morphogenetic and angiogenic genes such as BMP4, SMO, HOXA3, EPAS1 and FGFR2 were upregulated, reflecting the state of an activated endothelium. At later stages, a general decrease in gene expression occurs, including genes encoding mitotic factors or angiogenic mediators such as CYR61, EPAS1, MDK and MYC. We identified putative human orthologs for 77% of significantly regulated genes and determined endothelial cell enrichment for 20% of the orthologs in silico. Vascular expression of several genes including ENC1, FSTL1, JAM2, LDB2, LIMS1, PARVB, PDE3A, PRCP, PTRF and ST6GAL1 was demonstrated by in situ hybridization. Up to 9% of the CAM genes were also overexpressed in human organs with related functions, such as placenta and lung or the thyroid. 21-66% of CAM genes enriched in endothelial cells were deregulated in several human cancer types (P<.0001). Interfering with PARVB (encoding parvin, beta) function profoundly changed human endothelial cell shape, motility and tubulogenesis, suggesting an important role of this gene in the angiogenic process.
  
  
  CONCLUSIONS
  Our study underlines the complexity of gene regulation in a highly vascularized organ during development. We identified a restricted number of novel genes enriched in the endothelium of different species and tissues, which may play crucial roles in normal and pathological angiogenesis.
authors.affiliation: INSERM U920, Laboratoire des Mécanismes Moléculaires de l'Angiogenèse, Université Bordeaux 1, Talence, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Javerzat
authors.forename: Mélanie
authors.initials: M
authors.lastname: Franco
authors.forename: John
authors.initials: J
authors.lastname: Herbert
authors.forename: Natalia
authors.initials: N
authors.lastname: Platonova
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Peille
authors.forename: Véronique
authors.initials: V
authors.lastname: Pantesco
authors.forename: John
authors.initials: J
authors.lastname: De Vos
authors.forename: Said
authors.initials: S
authors.lastname: Assou
authors.forename: Roy
authors.initials: R
authors.lastname: Bicknell
authors.forename: Andreas
authors.initials: A
authors.lastname: Bikfalvi
authors.forename: Martin
authors.initials: M
authors.lastname: Hagedorn
mesh_terms: D000818:Animals; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000378:metabolism; D016000:Cluster Analysis; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008938:Mitosis; D008954:Models, Biological; D018919:Neovascularization, Physiologic; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors