Vascular wall maturation and prolonged angiogenic effect by endothelial-specific platelet-derived growth factor expression

Keren Levanon, Nira Varda-Bloom, Shoshana Greenberger, Iris Barshack, Iris Goldberg, Arie Orenstein, Eyal Breitbart, Aviv Shaish, Dror Harats

Research output: Contribution to journalArticlepeer-review

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 non-specific 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.

Original languageEnglish
Pages (from-to)149-158
Number of pages10
JournalPathobiology
Volume73
Issue number3
DOIs
StatePublished - 2006

Keywords

  • Adenovirus
  • Angiogenesis-inducing agents
  • Endothelin-1
  • Endothelium, vascular
  • Gene therapy
  • Ischemia
  • Murine model
  • Platelet-derived growth factor
  • Promoter regions
  • Vascular endothelial growth factor A

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