Obesity is a major risk factor for the development of hypertension. Recent studies have suggested that leptin, a 167-amino acid peptide hormone produced by white adipose tissue, is related to the pathogenesis of obesity-related hypertension. However, the signaling mechanisms underlying the effects of leptin remain to be extensively examined. In this study, we found that leptin induced extracellular signal-regulated kinase phosphorylation and endothelin-1 expression in rat aortic smooth muscle cells. Both PD98059 and U0126, inhibitors of the upstream activator of mitogen-activated protein kinase kinase, inhibited augmentation of endothelin-1 expression stimulated with leptin. Leptin induced significant tyrosine phosphorylation of epidermal growth factor receptor, which was significantly attenuated by two inhibitors, an epidermal growth factor receptor tyrosine kinase inhibitor, AG1478, and a broad-spectrum matrix metalloproteinase inhibitor, GM6001. This indicates that the pathway of epidermal growth factor receptor transactivation induced by leptin is dependent on proteolytically released epidermal growth factor receptor ligands. Pretreatment of cells with AG1478 significantly reduced the degree of phosphorylation of extracellular signal-regulated kinase and endothelin-1 expression. Our results reveal that epidermal growth factor receptor transactivation is involved in the leptin signaling pathway in vascular smooth muscle cells, which may be related to the increased risk of hypertension and other cardiovascular diseases in obese subjects.