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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:70.)
© 2007 American Heart Association, Inc.

Vascular Biology

Leptin Regulates Neointima Formation After Arterial Injury Through Mechanisms Independent of Blood Pressure and the Leptin Receptor/STAT3 Signaling Pathways Involved in Energy Balance

Peter F. Bodary; Yuechun Shen; Miina Öhman; Kristina L. Bahrou; Fernando B. Vargas; Sarah S. Cudney; Kevin J. Wickenheiser; Martin G. Myers, Jr; Daniel T. Eitzman

From the Divisions of Cardiovascular Medicine and Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor.

Correspondence to Daniel T. Eitzman, MD, 1150 W. Medical Center Dr, 7301 MSRB III, Ann Arbor, MI 48109-0644. E-mail deitzman{at}umich.edu

Background— Leptin is an adipocyte-derived hormone critical for energy homeostasis and implicated in vascular disease processes. The relevant cellular leptin receptor pools and signaling pathways involved in leptin-related vascular phenotypes in vivo are unclear.

Methods and Results— Arterial injury was induced in wild-type (wt), leptin-deficient (lep^ob/ob), and leptin receptor–deficient (lepr^db/db) mice. Compared with wt mice, lep^ob/ob and lepr^db/db mice were protected from the development of neointima. Bone marrow transplantation experiments between wt and lepr^db/db mice indicated that the vascular protection in lepr^db/db mice was not attributable to lack of leptin receptor expression on bone marrow–derived elements. To investigate the role of the lepr-mediated signal transducer and activator of transcription 3 (STAT3) signaling pathway in the response to vascular injury, lepr^s/s mice homozygous for a leptin receptor defective in STAT3 signaling underwent femoral arterial injury. Despite similar obesity and blood pressure levels, the neointimal area in lepr^s/s mice was significantly increased compared with lepr^db/db mice.

Conclusions— The molecular mechanism by which the leptin receptor mediates neointima formation and vascular smooth muscle cell proliferation is largely independent of the STAT3-dependent signaling pathways involved in energy balance.

Elevated levels of leptin have been associated with increased risk for cardiovascular disease. We demonstrate that mice deficient in leptin or leptin receptor are protected from neointimal formation. This effect is mediated by a non–bone marrow–derived leptin receptor pool and by signaling pathways independent of those responsible for energy balance.

Key Words: atherosclerosis • obesity • remodeling • restenosis

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