title: Therapeutic angiogenesis due to balanced single-vector delivery of VEGF and PDGF-BB.
abstract: Therapeutic angiogenesis by delivery of vascular growth factors is an attractive strategy for treating debilitating occlusive vascular diseases, yet clinical trials have thus far failed to show efficacy. As a result, limb amputation remains a common outcome for muscle ischemia due to severe atherosclerotic disease, with an overall incidence of 100 per million people in the United States per year. A challenge has been that the angiogenic master regulator vascular endothelial growth factor (VEGF) induces dysfunctional vessels, if expressed outside of a narrow dosage window. We tested the hypothesis that codelivery of platelet-derived growth factor-BB (PDGF-BB), which recruits pericytes, could induce normal angiogenesis in skeletal muscle irrespective of VEGF levels. Coexpression of VEGF and PDGF-BB encoded by separate vectors in different cells or in the same cells only partially corrected aberrant angiogenesis. In marked contrast, coexpression of both factors in every cell at a fixed relative level via a single bicistronic vector led to robust, uniformly normal angiogenesis, even when VEGF expression was high and heterogeneous. Notably, in an ischemic hindlimb model, single-vector expression led to efficient growth of collateral arteries, revascularization, increased blood flow, and reduced tissue damage. Furthermore, these results were confirmed in a clinically applicable gene therapy approach by adenoviral-mediated delivery of the bicistronic vector. We conclude that coordinated expression of VEGF and PDGF-BB via a single vector constitutes a novel strategy for harnessing the potency of VEGF to induce safe and efficacious angiogenesis.
authors.affiliation: Baxter Laboratory for Stem Cell Biology, Institute for Regenerative Medicine and Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, California 34305-5175, USA. abanfi@uhbs.ch
authors.forename: Andrea
authors.initials: A
authors.lastname: Banfi
authors.forename: Georges
authors.initials: G
authors.lastname: von Degenfeld
authors.forename: Roberto
authors.initials: R
authors.lastname: Gianni-Barrera
authors.forename: Silvia
authors.initials: S
authors.lastname: Reginato
authors.forename: Milton J
authors.initials: MJ
authors.lastname: Merchant
authors.forename: Donald M
authors.initials: DM
authors.lastname: McDonald
authors.forename: Helen M
authors.initials: HM
authors.lastname: Blau
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000077214:Becaplermin; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D057809:HEK293 Cells; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D018482:Muscle, Skeletal / Q000098:blood supply; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000627:therapeutic use; D020574:Proto-Oncogene Proteins c-sis / Q000008:administration & dosage / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D042461:Vascular Endothelial Growth Factor A; D000077214:Becaplermin