Investigation of systemic and paracrine effects of leptin on neointima formation after experimental vascular injury in the mouse model

Obesity is a very good known risk factor of atherothrombotic complications of the heart and the vessel system. Additionally growing bodyweight and elevated mass of the perivascular adipose tissue (PVAT) and visceral adipose tissue (VAT). In obesity state, these adipose tissues produce elevated levels of adipokines, respectivly as well the hormon leptin. High serum levels and elevated expression and paracrine secretion of leptin in the PVAT can possibly effect directly the adjacent vessel wall. With the help of mouse models three experimental groups with undergroups were created. Every mouse was subjected to a standardized operation of experimental vascular injury of the left common carotid artery. In the first group the systemical effect of leptin after vascular injury was investigated with and without hyperleptinemia. Significantly elevated neointima formation, showing restenosis, could determined. This effect couldn't recognized by systemical leptin deficiency. In the second group the paracrine effect of leptin was simulated by addition of adenoviral vectors including leptin- or control-cDNA around the artery after vascular injury. Leptin-dependent elevated neointima formation could be shown independent of bodyweight and systemic serum levels of leptin. In contrast, lowered neointima formation could demonstrated in leptin-receptor-deficient mice. However, a direct context between the paracrine effect of leptin and elevated neointima formation could be illustrated. In the third group a self developed transplantation model for VAT was applied to simulate "local overweight" around the injured artery under normal and leptin-deficient conditions. Higher significant neointima formation was the effect after transplantation of VAT from wild-type mice, which are undergoing a 8-week long high-fat diet before transplantation. After transplantion of VAT from leptin-deficient mice no elevation of neointima formation could illustrated. Interestingly, after transplantation VAT from leptin-deficient mice, undergoing a 8-week long high-fat diet, elevated neointima formation could illustrated as well. This, partly based on leptin, proatherosclerotic effect of the PVAT shows that there are more cytokines and mediators from the VAT and PVAT in obesity, which has vasoregulatory, metabolic and proatherogenic effects. Additionaly, in in-vitro examinations could demonstrated a, well known, positive effect of leptin on the proliferation of smooth muscle cells of the vessel wall. In conclusion, elevated concentrations of leptin in PVAT demonstrate an important risk factor for the development of atherosclerotic lesions of the vessel wall after vascular injury and these results describe the importance of local remodeling in PVAT as a possible reason for the elevated risk of cardiovascular diseases in obesity.2016-04-1