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

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Abstract
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.