In the absence of metabolic syndrome or diabetes II, obesity is only a weak risk factor for the development of cardiovascular diseases and endothelial dysfunction. We hypothesized that adipokines may contribute to maintain vascular function. Herein we focused on leptin and determined its effects beyond endothelial nitric oxidase synthase (eNOS).

Wildtype (WT) and eNOS^-/--mice were infused with or without leptin. Isolated vessel recordings in presence of diclofenac revealed that leptin treatment improved acetylcholine (ACh)-induced relaxation of aortic segments from eNOS^-/--mice. Blocking total NOS activity by L-nitro-arginine abolished the improved relaxation in response to ACh suggesting a NOS mediated effect of leptin-treatment. TRIM, a selective i/nNOS-inhibitor blocked the augmented endothelial relaxation in rings from eNOS^-/--mice by leptin. Accordingly in vivo leptin failed to enhance ACh-induced relaxation in segments from e/nNOS double knockout mice. Importantly leptin rescued angiotensin II induced endothelial dysfunction in a disease model where we infused WT-mice with or without leptin.

Quantitative PCR of human and murine isolated vessel segments revealed that nNOS expression was induced by leptin-treatment. In human endothelial cells, acute leptin stimulation increased Jak2, Stat3 and p38 phosphorylation, signals controlling nNOS expression. Pharmacological inhibition of Jak2/Stat3 or p38 pathway prevented leptin-induced nNOS expression in vessels. In contrast only blocking of Jak2/Stat3 but not of p38 prevented leptin-induced improvement of ACh-induced relaxation in vivo.

We conclude that leptin increases the vascular production of NO and thereby improves ACh-induced relaxation by induction of nNOS via the Jak2/Stat3-pathway.