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

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.

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).

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.

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.

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.