Abstract
Therapeutic angiogenesis by growth factor delivery is an attractive treatment strategy for ischemic diseases, yet clinical efficacy has been elusive. The angiogenic master regulator VEGF-A can induce aberrant angiogenesis if expressed above a threshold level. Since VEGF remains localized in the matrix around expressing cells, homogeneous dose distribution in target tissues is required, which is challenging. We found that co-expression of the pericyte-recruiting factor PDGF-BB at a fixed ratio with VEGF from a single bicistronic vector ensured normal angiogenesis despite heterogeneous high VEGF levels. Taking advantage of a highly controlled gene delivery platform, based on monoclonal populations of transduced myoblasts, in which every cell stably produces the same amount of each factor, here we rigorously investigated a) the dose-dependent effects, and b) the long-term safety and stability of VEGF and PDGF-BB co-expression in skeletal muscle. PDGF-BB co-expression did not affect the normal angiogenesis by low and medium VEGF doses, but specifically prevented vascular tumors by high VEGF, yielding instead normal and mature capillary networks, accompanied by robust arteriole formation. Induced angiogenesis persisted unchanged up to 4 months, while no tumors appeared. Therefore, PDGF-BB co-expression is an attractive strategy to improve safety and efficacy of therapeutic angiogenesis by VEGF gene delivery.
Highlights
Therapeutic angiogenesis by growth factor delivery is an attractive treatment strategy for ischemic diseases, yet clinical efficacy has been elusive
Here we took advantage of a highly controlled platform for sustained gene expression in skeletal muscle that we developed in the last decade[10,15], based on monoclonal populations of transduced myoblasts, in which every cell stably produces a specific amount of Vascular endothelial growth factor-A (VEGF) alone or at a fixed ratio with Platelet-derived growth factor-BB (PDGF-BB), to rigorously investigate a) the dose-dependent effects, and b) the long-term safety and stability of angiogenesis induced by balanced and constitutive co-expression of VEGF and PDGF-BB in the therapeutic target tissue of skeletal muscle
To rigorously study the dose-dependent effects of PDGF-BB co-expression on VEGF-induced angiogenesis, a pool of 90 monoclonal populations was isolated from the VIP polyclonal myoblasts (VIP clones)
Summary
Therapeutic angiogenesis by growth factor delivery is an attractive treatment strategy for ischemic diseases, yet clinical efficacy has been elusive. Sequential release of the two recombinant factors from hydrogels in ischemic mouse myocardium could increase the induction of mature arteriole-like vessels, without affecting capillary growth, leading to improved cardiac function[14] Based on these results, balanced co-expression of VEGF and PDGF-BB is a promising strategy to overcome the limitations of VEGF gene delivery in pro-angiogenic therapeutic approaches. Here we took advantage of a highly controlled platform for sustained gene expression in skeletal muscle that we developed in the last decade[10,15], based on monoclonal populations of transduced myoblasts, in which every cell stably produces a specific amount of VEGF alone or at a fixed ratio with PDGF-BB, to rigorously investigate a) the dose-dependent effects, and b) the long-term safety and stability of angiogenesis induced by balanced and constitutive co-expression of VEGF and PDGF-BB in the therapeutic target tissue of skeletal muscle
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