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FASEB J. 2012 Jun;26(6):2486-97. doi: 10.1096/fj.11-197400. Epub 2012 Mar 5.

Therapeutic angiogenesis due to balanced single-vector delivery of VEGF and PDGF-BB.

Author information

1
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

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.

PMID:
22391130
PMCID:
PMC3360154
DOI:
10.1096/fj.11-197400
[Indexed for MEDLINE]
Free PMC Article

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