Regulation by Leptin of Vascular Smooth Muscle Cells Proliferation and Migration

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Obesity is one of the major risk factors for cardiovascular diseases. However, less is yet known about the molecular mechanisms associating between obesity and cardiovascular diseases. The ob gene product, leptin has been defined as a regulator of food intake and energy expenditure. The receptors for leptin (OB-R) are widely expressed throughout the body, suggesting that, in addition to the control of food intake and body weight, leptin may have other important physiological functions. In obese patients, plasma leptin levels are elevated. Therefore, in this study, we investigated the effect of leptin on vascular smooth muscle cell (VSMC) functions. Cultured rat aortic VSMC expressed several isoforms of leptin receptors including 130-kDa short form. Leptin stimulated both proliferation and migration of VSMC. Leptin stimulated phosphorylation and activation of extracellular-regulated Kinase (ERK) isoformes of mitogen-activated protein (MAP) kinases, and also increased phosphatidylinositol (PI) 3-kinase activity in anti-phosphotyrosine immunoprecipitates in VSMC. Further, two distinct PI 3-kinase inhibitors, wortmannin and LY294002 inhibited the migratory effect of leptin, indicating the essential role of PI 3-kinase in leptin-stimulated migration of VSMC. These results demonstrate that leptin is a proliferative and migratory factor for VSMC, implying that leptin plays a role in the formation and development of vascular lesions.