VEGF‐D △N△C mediated angiogenesis in skeletal muscles of diabetic WHHL rabbits

Eur J Clin Invest 2010; 40 (5): 422–432 Abstract Background  Arterial occlusive disease is often associated with diabetes mellitus and hypercholesterolaemia which may reduce angiogenic potential of several growth factors. Accordingly, the usefulness of therapeutic angiogenesis in the presence of diabetes and hypercholesterolaemia has remained unclear. We evaluated angiogenic effects of the mature form of vascular endothelial growth factor‐D (VEGF‐D △N△C ) in skeletal muscles in the presence of severe diabetes and hypercholesterolaemia. Methods  Intra muscular injections of adenoviruses encoding human VEGF‐D △N△C (AdVEGF‐D △N△C ) were given in the hind limbs of a group of diabetic hypercholesterolaemic rabbits and adenoviruses encoding LacZ (AdLacZ) were used as a control. All animals were killed 6 days after the gene transfer. Results  Capillary count, capillary area, capillary permeability and perfusion were significantly higher in the AdVEGF‐D △N△C transduced muscles compared with the AdLacZ controls. Expressions of endothelial nitric oxide synthase (eNOS) and VEGF receptor(R)‐2 were also significantly increased in the VEGF‐D △N△C transduced muscles, along with an increased expression of angiopoietins (Angs) and neuropilin‐2 (NP‐2). Furthermore, VEGF‐D △N△C gene transfer to the skeletal muscles increased localized recruitment of cells with endothelial progenitor‐like characteristics. Conclusions  VEGF‐D △N△C gene transfer can induce efficient angiogenesis in the presence of severe diabetes and hypercholesterolaemia by upregulating eNOS and VEGFR‐2 expression. VEGF‐D △N△C appears to be a promising agent for inducing therapeutic angiogenesis even in cases with severe diabetes and hypercholesterolaemia.