Leptin Induces Sca-1+ Progenitor Cell Migration Enhancing Neointimal Lesions in Vessel-Injury Mouse Models
نویسندگان
چکیده
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.
منابع مشابه
Vascular Stem/Progenitor Cell Migration Induced by Smooth Muscle Cell‐Derived Chemokine (C‐C Motif) Ligand 2 and Chemokine (C‐X‐C motif) Ligand 1 Contributes to Neointima Formation
Recent studies have shown that Sca-1(+) (stem cell antigen-1) stem/progenitor cells within blood vessel walls may contribute to neointima formation, but the mechanism behind their recruitment has not been explored. In this work Sca-1(+) progenitor cells were cultivated from mouse vein graft tissue and found to exhibit increased migration when cocultured with smooth muscle cells (SMCs) or when t...
متن کاملCaspase-1 mediates hyperlipidemia-weakened progenitor cell vessel repair.
Caspase-1 activation senses metabolic danger-associated molecular patterns (DAMPs) and mediates the initiation of inflammation in endothelial cells. Here, we examined whether the caspase-1 pathway is responsible for sensing hyperlipidemia as a DAMP in bone marrow (BM)-derived Stem cell antigen-1 positive (Sca-(1+)) stem/progenitor cells and weakening their angiogenic ability. Using biochemical ...
متن کاملResveratrol Reduces Vessel-graft Neointimal Formation by Inducing Endothelial Differentiation of Resident Progenitor Cells through a Mir-21/akt/b-catenin Pathway
Background Vessel graft failure is typically associated neointimal formation and arteriosclerosis, in which endothelial dysfunction/ damage is a key event.1 Resveratrol has been shown to possess cardioprotective capacity and to reduce atherosclerosis, through its anti-oxidant and anti-apoptotic properties.2–4 However, it is unknown whether it influences the behavior of resident stem cells in th...
متن کاملResveratrol Reduces Vessel-graft Neointimal Formation by Inducing Endothelial Differentiation of Resident Progenitor Cells through a Mir-21/akt/b-catenin Pathway
Background Vessel graft failure is typically associated neointimal formation and arteriosclerosis, in which endothelial dysfunction/ damage is a key event.1 Resveratrol has been shown to possess cardioprotective capacity and to reduce atherosclerosis, through its anti-oxidant and anti-apoptotic properties.2–4 However, it is unknown whether it influences the behavior of resident stem cells in th...
متن کاملAdventitial SCA-1+ Progenitor Cell Gene Sequencing Reveals the Mechanisms of Cell Migration in Response to Hyperlipidemia
Adventitial progenitor cells, including SCA-1+ and mesenchymal stem cells, are believed to be important in vascular remodeling. It has been shown that SCA-1+ progenitor cells are involved in neointimal hyperplasia of vein grafts, but little is known concerning their involvement in hyperlipidemia-induced atherosclerosis. We employed single-cell sequencing technology on primary adventitial mouse ...
متن کامل