Background Leptin is a hormone that is predominantly secreted by white adipose tissue and thus the majority of obese individuals display high concentrations of plasma leptin. Initially believed to be solely a metabolic factor, leptin also plays a role in inflammation, vascular disease, to which Sca-1+ vascular progenitor cells within the vessel wall may contribute.

Hypothesis Leptin can influence neointimal formation by promoting the migration of Sca-1+ progenitor cells.

Methods and results Sca-1+ progenitor cells were cultivated from the vessel wall of apoE-/- mice and purified via microbeads. The cell migration assessments included transwell and wound healing assays in vitro. The migration of Sca-1+ progenitor cells was markedly induced by leptin in a dose-dependent manner (2.420±0.222 and 1.318±0.036). This migration induced by leptin was significantly inhibited by a leptin triple mutant antagonist CYT-566, ERK inhibitor or a STAT3 inhibitor. Western blot analysis revealed that leptin induced phosphorylation of STAT3 and ERK1/2, respectively, implicating the impact of these signal pathways. When applied the Sca-1+ progenitor cells from leptin receptor deficient mice for the experiments above, both the migratory ability and protein activation were markedly abolished. When endovascular injury was induced in wild-type mice by passing a 0.014 guidewire three times through the femoral artery, neointimal lesions were observed in a time-dependent manner. Immunostaining for leptin displayed an increased expression of leptin in the injured vessels. Serum ELISA for leptin assay demonstrated a peak increase at 24 hours after vessel injury. When red fluorescent protein (RFP) labelled-Sca-1+ progenitor cells in Matrigel were applied to the adventitia of the injured femoral artery, REP+ cells were observed in the intimal 24 hours post-operation, which significantly enhanced neointimal lesions at 2 weeks. This increased neointimal lesion was rescued by pre-treatment of Sca-1+ cells with leptin antagonist CYT-566. In addition, when wild-type Sca-1+ progenitor cells were delivered to the adventitia of the injured artery in leptin receptor deficient mice, a significant increased neointimal formation was observed at 2 weeks, indicating crucial roles of leptin receptor and Sca-1+ progenitor cells in vascular remodelling.

Conclusions-Levels of leptin in both the vessel wall and the circulation are upregulated after vessel injury, leading to the migration of Sca-1+ progenitor cells that enhances neointimal formation.