title: HoxB5 induces endothelial sprouting in vitro and modifies intussusceptive angiogenesis in vivo involving angiopoietin-2.
abstract: OBJECTIVE
  Homeobox (Hox) proteins are transcriptional regulators in embryonic patterning, cell differentiation, proliferation, and migration in vertebrates and invertebrates. A growing body of evidence suggests that Hox proteins are involved in endothelial cell regulation. We have shown earlier that HoxB5 upregulates vascular endothelial growth factor receptor-2 and thereby contributes to enhanced endothelial precursor cell differentiation. Here we aim to elucidate the role of HoxB5 in angiogenesis.
  
  
  RESULTS
  Endothelial cell sprouting was investigated in the human umbilical vein endothelial cell spheroid assay. We investigated in vivo angiogenesis in the chick (Gallus gallus) chorioallantoic membrane assay. Expression profiling of proangiogenic factors was done by quantitative PCR. The angiopoietin-2 (Ang2) promoter and deletion fragments thereof were cloned into the pGL3 reporter system for analysis of transcriptional activity. We observed that HoxB5 enhances endothelial cell sprouting and modulates the expression of adhesion molecules in vitro. Accordingly, we observed a modification of vascular growth by HoxB5 in vivo. The HoxB5 effect is reminiscent of the effects of angiopoietins. We demonstrate that Ang2 is upregulated upon HoxB5 overexpression and that the HoxB5 effect is abolished by the angiopoietin antagonist soluble Tie-2.
  
  
  CONCLUSIONS
  HoxB5 has an activating effect on Ang2 that is essential for endothelial cell sprouting and coordinated vascular growth.
authors.affiliation: Department of Cardiology, University of Freiburg, Hugstetter Strasse 55, Freiburg 79106, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Winnik
authors.forename: Mei
authors.initials: M
authors.lastname: Klinkert
authors.forename: Haymo
authors.initials: H
authors.lastname: Kurz
authors.forename: Christoph
authors.initials: C
authors.lastname: Zoeller
authors.forename: Jennifer
authors.initials: J
authors.lastname: Heinke
authors.forename: Yaxu
authors.initials: Y
authors.lastname: Wu
authors.forename: Christoph
authors.initials: C
authors.lastname: Bode
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.forename: Martin
authors.initials: M
authors.lastname: Moser
mesh_terms: D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply*; D053595:Embryonic Stem Cells / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018919:Neovascularization, Physiologic / Q000235:genetics; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D042787:Receptor, TIE-2 / Q000378:metabolism; D014161:Transduction, Genetic; D015854:Up-Regulation
chemical_list: D042702:Angiopoietin-2; D015815:Cell Adhesion Molecules; D018398:Homeodomain Proteins; D042787:Receptor, TIE-2