Methylglyoxal administration induces diabetes-like microvascular changes and perturbs the healing process of cutaneous wounds.

Increased formation of MG (methylglyoxal) and related protein glycation in diabetes has been linked to the development of diabetic vascular complications. Diabetes is also associated with impaired wound healing. In the present study, we investigated if prolonged exposure of rats to MG (50-75 mg/kg of body weight) induced impairment of wound healing and diabetes-like vascular damage. MG treatment arrested growth, increased serum creatinine, induced hypercholesterolaemia (all P < 0.05) and impaired vasodilation (P < 0.01) compared with saline controls. Degenerative changes in cutaneous microvessels with loss of endothelial cells, basement membrane thickening and luminal occlusion were also detected. Acute granulation appeared immature (P < 0.01) and was associated with an impaired infiltration of regenerative cells with reduced proliferative rates (P < 0.01). Immunohistochemical staining indicated the presence of AGEs (advanced glycation end-products) in vascular structures, cutaneous tissue and peripheral nerve fibres. Expression of RAGE (receptor for AGEs) appeared to be increased in the cutaneous vasculature. There were also pro-inflammatory and profibrotic responses, including increased IL-1beta (interleukin-1beta) expression in intact epidermis, TNF-alpha (tumour necrosis factor-alpha) in regions of angiogenesis, CTGF (connective tissue growth factor) in medial layers of arteries, and TGF-beta (transforming growth factor-beta) in glomerular tufts, tubular epithelial cells and interstitial endothelial cells. We conclude that exposure to increased MG in vivo is associated with the onset of microvascular damage and other diabetes-like complications within a normoglycaemic context.

Intramyocardial gene transfer of vascular endothelial growth factor 121 improves myocardial perfusion and function in the ischemic porcine heart

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen that is angiogenic in vitro and in vivo. Several studies report on gene transfer of VEGF121 to promote angiogenesis in the ischemic myocardium of animals and patients. We hypothesized that intramyocardial administration of naked plasmid DNA encoding VEGF121 could improve myocardial perfusion and function in a porcine model of myocardial ischemia. Yorkshire swine underwent thoracotomy and placement of an ameroid constrictor on the circumflex coronary artery. Four weeks later, pVEGF121 plasmid was administered into the ischemic myocardium. Four weeks after gene transfer, SPECT imaging demonstrated significant reduction in the ischemic area in pVEGF121-treated animals compared with controls. In the pVEGF121 group, most of the animals evolved from light ischemia to a normal perfusion. In contrast, control animals exhibited similar or impaired ischemic conditions. Our results indicate that intramyocardial gene transfer of VEGF121 as naked plasmid DNA results in significant improvement in myocardial perfusion and function.