Autologous vein grafts is still commonly used for arterial reconstructive procedures. Their success is limited by the development of neointimal hyperplasia. Clinical and experimental evidence suggest that the bone marrow derived mesenchymal stem cells (MSCs) participate in the neovascularization. The current study used a direct approach to test the hypothesis that, after vein grafting in a rat model, MSCs have potential effects on reendothelialization and neointimal formation. MSCs were isolated by bone marrow cell adherence. Autologously interpositioning left external jugular vein (LEJV) to left common carotid artery-induced vein grafting model of r at w as utilized. Vascular lesion formation after transplantation of MSCs labeled with 4',6-diamidino-2-phenylindole (DAPI) was investigated. Two weeks after implantation, immunofluorescence studies revealed that engrafted cells acquired an endothelial phenotype, and some expressed endothelial nitric oxide synthase (eNOS). Furthermore, proliferation of cells and neointimal formation decreased significantly after MSC implantation. Real-time reverse transcription-PCR and western blotting analysis showed a rise of eNOS expression in the MSC group compared with the vein grafting group. Therefore, engrafted MSCs appeared to differentiate into endothelial cells, diminish the neointima formation and contribute to the improvement on endothelial function, which indicates that MSCs may exert an important function as repair mechanism in vascular injury after vein grafting.
To date, hypoxia-inducible factor 1a (HIF-1a) and astrocyte elevated gene-1 (AEG-1) have been involved in the proliferation, migration and morphological changes of vascular smooth muscle cells. However, the potential relationship of HIF-1a-AEG-1 pathway in human aortic smooth muscle cell (HASMC) has not been reported. In the present study, in-vitro assays were utilized to explore the potential impact of HIF-1a-AEG-1 signaling on HASMC phenotype. Here, we found that HIF-1a expression was up-regulated in the media of thoracic aortic dissection tissues as compared with normal aortic tissues, and was associated with increased apoptotic SMCs and decreased AEG-1 expression. Mechanically, hypoxia promoted the expression of HIF-1a by PI3K-AKT pathway in HASMCs; HIF-1a further suppressed the expressions of AEG-1, a-SMA and SM22a, and promoted osteopontin (OPN) expression. Functionally, HIF-1a inhibited the proliferation and migration of HASMCs. However, si-HIF-1a or Akt inhibitor abrogated HIF-1a-mediated related expressions and biological effects above. In conclusion, HIF-1a induces HASMC phenotype switch, and closely related to PI3K/AKT and AEG-1 signaling, which may provide new avenues for the prevention and treatment of aortic dissection diseases.
Bone marrow‐derived mesenchymal stem cells (BMSCs) have great therapeutic potential for many diseases. However, the homing of BMSCs to injury sites remains a difficult problem. Recent evidence indicates that simvastatin stimulates AKT phosphorylation, and p‐AKT affects the expression of chemokine (CXC motif) receptor‐4 (CXCR4). Therefore, simvastatin may improve the expression of CXCR4 in BMSCs, and microRNAs (miRs) may participate in this process. In this study, we demonstrated that simvastatin increased both the total and the surface expression of CXCR4 in BMSCs. Stromal cell‐derived factor‐1α (SDF‑1α)‐induced migration of BMSCs was also enhanced by simvastatin, and this action was inhibited by AMD 3100(a chemokine receptor antagonist for CXCR4). The PI3K/AKT pathway was activated by simvastatin in this process, and LY294002 reversed the overexpression of CXCR4 caused by simvastatin. MiR‐9 directly targeted CXCR4 in rat BMSCs, and simvastatin decreased miR‐9 expression. P‐AKT affected the expression of miR‐9; as the phosphorylation of AKT increased, miR‐9 expression decreased. In addition, LY294002 increased miR‐9 expression. Taken together, our results indicated that simvastatin improved the migration of BMSCs via the PI3K/AKT pathway. MiR‐9 also participated in this process, and the phosphorylation of AKT affected miR‐9 expression, suggesting that simvastatin might have beneficial effects in stem cell therapy.
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