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Arterioscler Thromb Vasc Biol. 2017 Nov;37(11):2114-2127. doi: 10.1161/ATVBAHA.117.309852. Epub 2017 Sep 21.

Leptin Induces Sca-1+ Progenitor Cell Migration Enhancing Neointimal Lesions in Vessel-Injury Mouse Models.

Author information

1
From the Cardiovascular Division, King's College London BHF Centre, United Kingdom (Y.X., C.M.F.P., W.N.N., A.L.B., W.G., S.I.B., Z.Z., Y.H., Q.X.); and Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, China (L.Z.).
2
From the Cardiovascular Division, King's College London BHF Centre, United Kingdom (Y.X., C.M.F.P., W.N.N., A.L.B., W.G., S.I.B., Z.Z., Y.H., Q.X.); and Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, China (L.Z.). qingbo.xu@kcl.ac.uk yanhua.hu@kcl.ac.uk.

Abstract

OBJECTIVE:

Leptin is an adipokine initially thought to be a metabolic factor. Recent publications have shown its roles in inflammation and vascular disease, to which Sca-1+ vascular progenitor cells within the vessel wall may contribute. We sought to elucidate the effects of leptin on Sca-1+ progenitor cells migration and neointimal formation and to understand the underlying mechanisms.

APPROACH AND RESULTS:

Sca-1+ progenitor cells from the vessel wall of Lepr+/+ and Lepr-/- mice were cultured and purified. The migration of Lepr+/+ Sca-1+ progenitor cells in vitro was markedly induced by leptin. Western blotting and kinase assays revealed that leptin induced the activation of phosphorylated signal transducer and activator of transcription 3, phosphorylated extracellular signal-regulated kinases 1/2, pFAK (phosphorylated focal adhesion kinase), and Rac1 (ras-related C3 botulinum toxin substrate 1)/Cdc42 (cell division control protein 42 homolog). In a mouse femoral artery guidewire injury model, an increased expression of leptin in both injured vessels and serum was observed 24 hours post-surgery. RFP (red fluorescent protein)-Sca-1+ progenitor cells in Matrigel were applied to the adventitia of the injured femoral artery. RFP+ cells were observed in the intima 24 hours post-surgery, subsequently increasing neointimal lesions at 2 weeks when compared with the arteries without seeded cells. This increase was reduced by pre-treatment of Sca-1+ cells with a leptin antagonist. Guidewire injury could only induce minor neointima in Lepr-/- mice 2 weeks post-surgery. However, transplantation of Lepr+/+ Sca-1+ progenitor cells into the adventitial side of injured artery in Lepr-/- mice significantly enhanced neointimal formation.

CONCLUSIONS:

Upregulation of leptin levels in both the vessel wall and the circulation after vessel injury promoted the migration of Sca-1+ progenitor cells via leptin receptor-dependent signal transducer and activator of transcription 3- Rac1/Cdc42-ERK (extracellular signal-regulated kinase)-FAK pathways, which enhanced neointimal formation.

KEYWORDS:

adipokines; adventitia; leptin; mice; neointima

PMID:
28935755
PMCID:
PMC5671780
DOI:
10.1161/ATVBAHA.117.309852
[Indexed for MEDLINE]
Free PMC Article

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