Platelet-derived growth factor C promotes revascularization in ischemic limbs of diabetic mice

Abstract

Platelet-derived growth factor C (PDGF-C) has been reported to promote angiogenesis independently of vascular endothelial growth factor (VEGF), although its significance in postnatal angiogenesis in vivo remains poorly understood. VEGF has been employed as a major molecular tool to induce therapeutic angiogenesis. However, VEGF therapy is not very effective in models of cardiovascular diseases associated with diabetes, and the mechanisms of this phenomenon still remain to be elucidated. We used a murine model of hind limb ischemia and of streptozotocin-induced diabetes. Expression of PDGF-C and its receptor PDGFR-α were markedly upregulated in ischemic limbs. Treatment with a neutralizing antibody against PDGF-C significantly impaired blood flow recovery and neovascularization after ischemia almost to the same extent as a VEGF-neutralizing antibody. Mice deficient in PDGF-C exhibited reduced blood flow recovery after ischemia compared with wild-type mice, confirming a strong proangiogenic activity of PDGF-C. Next, we injected an expression vector encoding PDGF-C into ischemic limbs. Blood flow recovery and neovascularization after ischemia were significantly improved in the groups treated with PDGF-C compared with controls. Attenuation of angiogenic responses to ischemia has been reported in patients with diabetes even after VEGF treatment, although a precise mechanism remains unknown. We hypothesized that PDGF-C might relate to the impaired angiogenesis of diabetes. We tested this hypothesis by inducing diabetes by intraperitoneal injection of streptozotocin. Expression levels of PDGF-C at baseline and after ischemia were significantly lower in limb tissues of diabetic mice than in those of control mice, whereas expression levels of other members of the PDGF family and VEGF were not changed or were even higher in diabetic mice. Introduction of VEGF complementary DNA expression plasmid vector into ischemic limbs did not improve blood flow recovery. However, these changes were effectively reversed by additional introduction of the PDGF-C complementary DNA plasmid vector. These results indicate that downregulation of PDGF-C expression in limb tissues of diabetic mice contributes to impaired angiogenesis and suggest that introduction of PDGF-C might be a novel strategy for therapeutic angiogenesis, especially in the diabetic state. Angiogenesis and arteriogenesis after ischemia are attenuated in most diabetic patients, although the precise mechanisms remain unclear. Platelet-derived growth factors (PDGFs) have a variety of functions on many cell types, and PDGF-C stimulates angiogenesis and revascularizes ischemic tissues. This study indicates the role for PDGF-C as a critical regulator of impaired angiogenesis of diabetes and suggests that PDGF-C might be a novel target for the treatment of ischemic cardiovascular diseases in diabetes.