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Sitagliptin Stimulates Endothelial Progenitor Cells to Induce Endothelialization in Aneurysm Necks Through the SDF-1/CXCR4/NRF2 Signaling Pathway.

ABSTRACT: Aneurysm (AN) embolization is an important treatment for cerebral aneurysms. The endothelialization of the aneurysm neck is crucial for preventing aneurysm recurrence. Sitagliptin is a therapeutic drug for diabetes that has been reported to have cardiovascular-protective effects. This study investigated the effect of sitagliptin on endothelial progenitor cell (EPC) function and endothelialization of aneurysm necks after embolization. The effect of sitagliptin on aneurysm neck endothelialization was examined using a rat aneurysm embolization model. We isolated EPCs and used CCK-8 (Cell Counting Kit-8) and annexin V/PI to analyze the effect of sitagliptin on the proliferation and apoptosis of EPCs. The effects of sitagliptin on the migration and invasion of EPCs were examined using scratch and Transwell assays. The effect of sitagliptin on the angiogenic ability of EPCs was examined using a sprouting assay. Western blot analysis and ELISA were used to analyze the effect of sitagliptin on the expression of proangiogenic factors in EPCs. The in vivo results indicated that sitagliptin promoted endothelialization of the aneurysm neck and increased circulating EPCs and expression levels of SDF-1 and VEGF in peripheral blood. Sitagliptin promoted the proliferation, migration, invasion, and angiogenic abilities of EPCs. Western blot analysis and ELISA showed that sitagliptin promoted the expression of SDF-1 and VEGF in progenitor endothelial cells. Western blot assays showed that sitagliptin activated the expression of NRF2, which is dependent on the function of CXCR4. Furthermore, sitagliptin promoted progenitor endothelial cell migration, invasion and angiogenesis through the SDF-1/CXCR4/NRF2 signaling pathway. Additionally, progenitor endothelial cells expressed SDF-1 and VEGF. The promotion of endothelialization by sitagliptin provides an additional therapeutic option for preventing the recurrence of AN.

SUBMITTER: Yu G

PROVIDER: S-EPMC6988800 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Sitagliptin Stimulates Endothelial Progenitor Cells to Induce Endothelialization in Aneurysm Necks Through the SDF-1/CXCR4/NRF2 Signaling Pathway.

Yu Guo G Liu Peixi P Shi Yuan Y Li Sichen S Liu Yingjun Y Zhu Wei W

Frontiers in endocrinology 20191126

Aneurysm (AN) embolization is an important treatment for cerebral aneurysms. The endothelialization of the aneurysm neck is crucial for preventing aneurysm recurrence. Sitagliptin is a therapeutic drug for diabetes that has been reported to have cardiovascular-protective effects. This study investigated the effect of sitagliptin on endothelial progenitor cell (EPC) function and endothelialization of aneurysm necks after embolization. The effect of sitagliptin on aneurysm neck endothelialization ...[more]

PMID: 32038475

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Project description:Unlabelled: This study explored a new approach to enhance aneurysm (AN) neck endothelialization via erythropoietin (EPO)-induced endothelial progenitor cell (EPC) stimulation. Results suggest that EPO enhanced the endothelialization of a coiled embolization AN neck by stimulating EPCs via vascular endothelial growth factor modulation. Thus, the promotion of endothelialization with EPO provides an additional therapeutic option for preventing the recurrence of ANs. Endovascular coil embolization is an attractive therapy for cerebral ANs, but recurrence is a main problem affecting long-term outcomes. In this study, we explored a new approach to enhance AN neck endothelialization via EPO-induced EPC stimulation. Ninety adult male Sprague-Dawley rats were selected for an in vivo assay, and 60 of them underwent microsurgery to create a coiled embolization AN model. The animals were treated with EPO, and endothelial repair was assessed via flow cytometry, immunofluorescence, electronic microscopy, cytokine detection, and routine blood work. EPO improved the viability, migration, cytokine modulation, and gene expression of bone marrow-derived EPCs and the results showed that EPO increased the number of circulating EPCs and improved endothelialization compared with untreated rats (p < .05). EPO had no significant effect on the routine blood work parameters. In addition, the immunofluorescence analysis showed that the number of KDR(+) cells in the AN neck was elevated in the EPO-treated group (p < .05). Further study demonstrated that EPO promoted EPC viability and migration in vitro. The effects of EPO may be attributed to the modulation of vascular endothelial growth factor (VEGF). In particular, EPO enhanced the endothelialization of a coiled embolization AN neck by stimulating EPCs via VEGF modulation. Thus, the promotion of endothelialization with EPO provides an additional therapeutic option for preventing the recurrence of ANs.SignificanceErythropoietin (EPO) is involved in erythropoiesis and related conditions and is reported to enhance stem-cell mobilization from bone marrow while elevating stem-cell viability and function. In this study, EPO was also found to stimulate endothelial progenitor cells to induce the endothelialization of a coiled embolic aneurysm neck via vascular endothelial growth factor modulation. Endothelialization induction provides an additional therapeutic opportunity during vascular inner layer repair and remodeling. The results provide important information on the unique role EPO plays during vascular repair and remodeling.

Project description:BackgroundAdministration of endothelial progenitor cells (EPC) represents a promising option to regenerate the heart after myocardial infarction, but is limited because of low recruitment and engraftment in the myocardium. Mobilization and migration of EPC are mainly controlled by stromal cell-derived factor 1? (SDF-1?) and its receptor CXCR4. We hypothesized that adenosine, a cardioprotective molecule, may improve the recruitment of EPC to the heart.MethodsEPC were obtained from peripheral blood mononuclear cells of healthy volunteers. Expression of chemokines and their receptors was evaluated using microarrays, quantitative PCR, and flow cytometry. A Boyden chamber assay was used to assess chemotaxis. Recruitment of EPC to the infarcted heart was evaluated in rats after permanent occlusion of the left anterior descending coronary artery.ResultsMicroarray analysis revealed that adenosine modulates the expression of several members of the chemokine family in EPC. Among these, CXCR4 was up-regulated by adenosine, and this result was confirmed by quantitative PCR (3-fold increase, P<0.001). CXCR4 expression at the cell surface was also increased. This effect involved the A(2B) receptor. Pretreatment of EPC with adenosine amplified their migration towards recombinant SDF-1? or conditioned medium from cardiac fibroblasts. Both effects were abolished by CXCR4 blocking antibodies. Adenosine also increased CXCR4 under ischemic conditions, and decreased miR-150 expression. Binding of miR-150 to the 3' untranslated region of CXCR4 was verified by luciferase assay. Addition of pre-miR-150 blunted the effect of adenosine on CXCR4. Administration of adenosine to rats after induction of myocardial infarction stimulated EPC recruitment to the heart and enhanced angiogenesis.ConclusionAdenosine increases the migration of EPC. The mechanism involves A(2B) receptor activation, decreased expression of miR-150 and increased expression of CXCR4. These results suggest that adenosine may be used to enhance the capacity of EPC to revascularize the ischemic heart.

Dataset Information

Sitagliptin Stimulates Endothelial Progenitor Cells to Induce Endothelialization in Aneurysm Necks Through the SDF-1/CXCR4/NRF2 Signaling Pathway.

Publications

Sitagliptin Stimulates Endothelial Progenitor Cells to Induce Endothelialization in Aneurysm Necks Through the SDF-1/CXCR4/NRF2 Signaling Pathway.

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