title: Vascular wall maturation and prolonged angiogenic effect by endothelial-specific platelet-derived growth factor expression.
abstract: BACKGROUND
  The implementation of angiogenic gene therapy at clinics is hindered by the transience of the therapeutic effect. Recruiting vascular wall smooth muscle cells, a process termed 'maturation', can stabilize newly formed vessels.
  
  
  OBJECTIVE
  To induce angiogenesis followed by vessel maturation in a murine ischemic limb model by endothelial cell-specific promoter regulated expression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor-BB (PDGF-BB).
  
  
  METHODS
  We constructed adenoviral vectors containing angiogenic factors VEGF and PDGF-B regulated by a modified preproendothelin-1 (PPE-1-3x) promoter and investigated their angiogenic effect in a murine ischemic limb model.
  
  
  RESULTS
  VEGF gene therapy increased perfusion and the vessel density in the limb shortly after expression with PPE-1-3x promoter or cytomegalovirus (CMV) promoter vectors, but only PPE-1-3xVEGF treatment exhibited a sustained effect. Expression of PDGF-B by PPE-1-3x promoter resulted in morphological maturation of the vasculature and further increased the perfusion, while nonspecific expression of PDGF-B with CMV promoter had no therapeutic effect. Regulation of dual therapy with VEGF and PDGF-B by PPE-1-3x promoter resulted in an early-onset, sustained angiogenic effect accompanied by vessel maturation.
  
  
  CONCLUSIONS
  Systemic gene therapy with the angiogenic factors VEGF and PDGF-B under angiogenic- endothelial cell-specific regulation was effective in inducing functionally and morphologically mature vasculature.
authors.affiliation: Institute of Lipids and Atherosclerosis Research, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Keren
authors.initials: K
authors.lastname: Levanon
authors.forename: Nira
authors.initials: N
authors.lastname: Varda-Bloom
authors.forename: Shoshana
authors.initials: S
authors.lastname: Greenberger
authors.forename: Iris
authors.initials: I
authors.lastname: Barshack
authors.forename: Iris
authors.initials: I
authors.lastname: Goldberg
authors.forename: Arie
authors.initials: A
authors.lastname: Orenstein
authors.forename: Eyal
authors.initials: E
authors.lastname: Breitbart
authors.forename: Aviv
authors.initials: A
authors.lastname: Shaish
authors.forename: Dror
authors.initials: D
authors.lastname: Harats
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000818:Animals; D000077214:Becaplermin; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D006614:Hindlimb / Q000098:blood supply / Q000473:pathology / Q000601:surgery; D007150:Immunohistochemistry; D007511:Ischemia / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000235:genetics*; D010982:Platelet-Derived Growth Factor / Q000235:genetics* / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D043925:Angiogenesis Inducing Agents; D019332:Endothelin-1; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000077214:Becaplermin