Abstract
Vascular progenitors such as endothelial progenitor cells (EPCs) and smooth muscle-like progenitor cells (SMPCs) may play different roles in vascular repair. Ginkgo biloba extract (GBE) is an exogenous activator of heme oxygenase (HO)-1, which has been suggested to improve vascular repair; however, the detailed mechanisms have yet to be elucidated. This study aimed to investigate whether GBE can modulate different vascular progenitor cells by activating HO-1 for vascular repair. A bone marrow transplantation mouse model was used to evaluate the in vivo effects of GBE treatment on wire-injury induced neointimal hyperplasia, which is representative of impaired vascular repair. On day 14 of GBE treatment, the mice were subjected to wire injury of the femoral artery to identify vascular reendothelialization. Compared to the mice without treatment, neointimal hyperplasia was reduced in the mice that received GBE treatment for 28 days in a dose-dependent manner. Furthermore, GBE treatment increased bone marrow-derived EPCs, accelerated endothelial recovery, and reduced the number of SMPCs attached to vascular injury sites. The effects of GBE treatment on neointimal hyperplasia could be abolished by co-treatment with zinc protoporphyrin IX, an HO-1 inhibitor, suggesting the in vivo role of HO-1. In this in vitro study, treatment with GBE activated human early and late EPCs and suppressed SMPC migration. These effects were abolished by HO-1 siRNA and an HO-1 inhibitor. Furthermore, GBE induced the expression of HO-1 by activating PI3K/Akt/eNOS signaling in human late EPCs and via p38 pathways in SMPCs, suggesting that GBE can induce HO-1 in vitro through different molecular mechanisms in different vascular progenitor cells. Accordingly, GBE could activate early and late EPCs, suppress the migration of SMPCs, and improve in vivo vascular repair after mechanical injury by activating HO-1, suggesting the potential role of pharmacological HO-1 activators, such as GBE, for vascular protection in atherosclerotic diseases.
Highlights
Accumulating evidence suggests that circulating progenitor cells contribute to vascular healing and remodeling in response to vascular injury[1,2,3,4]
Ginkgo biloba extract (GBE) induced the expression of heme oxygenase (HO)-1 differentially through Phosphoinositide 3-kinase (PI3K)/AKT/endothelial nitric oxide synthase (eNOS) pathways in the late endothelial progenitor cells (EPCs) and via p38-related mechanisms in the smooth muscle-like progenitor cells (SMPCs)
GBE induced the expression of HO-1 and reduced the proliferation and migration of SMPCs, and this could be blocked by the presence of SB2003580, which is a p38 inhibitor, but not by LY294002, which is a PI3K/Akt inhibitor
Summary
Accumulating evidence suggests that circulating progenitor cells contribute to vascular healing and remodeling in response to vascular injury[1,2,3,4]. The participation of vascular progenitor cells in vascular repair is impaired by www.nature.com/scientificreports factors such as advanced age, diabetes mellitus, hypertension, and smoking In such conditions, vascular progenitor cells can differentiate into vascular smooth muscle cells (VSMCs) or macrophages, thereby promoting the formation of atherosclerotic lesions instead of vascular repair at the site of injury[6,7]. Early EPCs have been shown to act as cytokine donors, and a hindlimb ischemia model of mechanical injury and vascular regeneration showed that late EPCs could replace damaged endothelial cells[12,13,14]. Several growth factors, including vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1, are secreted into the circulation at the sites of vascular injury These growth factors serve as chemoattractants for the recruitment of bone marrow-derived vascular progenitor cells[17,18,19]. We conducted this study to test the hypothesis that HO-1 induced by GBE may modulate different vascular progenitor cells for vascular repair
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