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CXCR4信号受损导致冠心病患者内皮祖细胞的新生血管形成能力降低。

Impaired CXCR4 signaling contributes to the reduced neovascularization capacity of endothelial progenitor cells from patients with coronary artery disease.

作者信息

Walter Dirk H, Haendeler Judith, Reinhold Johannes, Rochwalsky Ulrich, Seeger Florian, Honold Jörg, Hoffmann Jörg, Urbich Carmen, Lehmann Ralf, Arenzana-Seisdesdos Fernando, Aicher Alexandra, Heeschen Christopher, Fichtlscherer Stephan, Zeiher Andreas M, Dimmeler Stefanie

机构信息

Molecular Cardiology, Department of Internal Medicine III, University of Frankfurt, Frankfurt, Germany.

出版信息

Circ Res. 2005 Nov 25;97(11):1142-51. doi: 10.1161/01.RES.0000193596.94936.2c. Epub 2005 Oct 27.

Abstract

Transplantation of bone marrow cells as well as circulating endothelial progenitor cells (EPC) enhances neovascularization after ischemia. The chemokine receptor CXCR4 is essential for migration and homing of hematopoietic stem cells. Therefore, we investigated the role of CXCR4 and its downstream signaling cascade for the angiogenic capacity of cultured human EPC. Ex vivo, differentiated EPC derived from peripheral blood abundantly expressed CXCR4. Incubation of EPC from healthy volunteers with neutralizing antibodies against CXCR4 profoundly inhibited vascular endothelial growth factor- and stromal-derived factor-1-induced migration as well as EPC-induced angiogenesis in an ex vivo assay. Preincubation of transplanted EPC with CXCR4 antibody reduced EPC incorporation and impaired blood-flow recovery in ischemic hindlimbs of nude mice (57+/-4% of normal perfusion versus untreated EPC: 80+/-11%, P<0.001). Bone marrow mononuclear cells (BM-MNC) or EPC of heterozygous CXCR4(+/-) mice displayed reduced CXCR4 expression and disclosed impaired in vivo capacity to enhance recovery of ischemic blood flow in nude mice (blood flow 27+/-11% versus 66+/-25% using wild-type cells, P<0.01). Importantly, impaired blood flow in ischemic CXCR4(+/-) mice was rescued by injection of wild-type BM-MNC. Next, we investigated the role of CXCR4 for functional capacities of EPC from patients with coronary artery disease (CAD). Surface expression of CXCR4 was similar in EPC from patients with CAD compared with healthy controls. However, basal Janus kinase (JAK)-2 phosphorylation was significantly reduced and less responsive to stromal-derived factor-1 in EPC from patients with CAD compared with healthy volunteers, indicating that CXCR4-mediated JAK-2 signaling is dysregulated in EPC from patients with CAD. The CXCR4 receptor signaling profoundly modulates the angiogenic activity and homing capacity of cultured human EPC. Disturbance of CXCR4 signaling, as demonstrated by reduced JAK-2 phosphorylation, may contribute to functional impairment of EPC from patients with CAD. Stimulating CXCR4 signaling might improve functional properties of EPC and may rescue impaired neovascularization capacity of EPC derived from patients with CAD.

摘要

骨髓细胞以及循环内皮祖细胞(EPC)的移植可增强缺血后的新生血管形成。趋化因子受体CXCR4对造血干细胞的迁移和归巢至关重要。因此,我们研究了CXCR4及其下游信号级联反应对培养的人EPC血管生成能力的作用。在体外,源自外周血的分化EPC大量表达CXCR4。用抗CXCR4的中和抗体孵育健康志愿者的EPC,在体外试验中可显著抑制血管内皮生长因子和基质衍生因子-1诱导的迁移以及EPC诱导的血管生成。用CXCR4抗体预孵育移植的EPC可减少EPC的掺入,并损害裸鼠缺血后肢的血流恢复(正常灌注的57±4%,而未处理的EPC为80±11%,P<0.001)。杂合CXCR4(+/-)小鼠的骨髓单个核细胞(BM-MNC)或EPC显示CXCR4表达降低,并揭示其在体内增强裸鼠缺血血流恢复的能力受损(血流为27±11%,而使用野生型细胞时为66±25%,P<0.01)。重要的是,通过注射野生型BM-MNC可挽救缺血CXCR4(+/-)小鼠受损的血流。接下来,我们研究了CXCR4对冠状动脉疾病(CAD)患者EPC功能的作用。与健康对照相比,CAD患者EPC中CXCR4的表面表达相似。然而,与健康志愿者相比,CAD患者EPC中的基础Janus激酶(JAK)-2磷酸化显著降低,且对基质衍生因子-1的反应性较低,表明CAD患者EPC中CXCR4介导的JAK-2信号失调。CXCR4受体信号深刻调节培养的人EPC的血管生成活性和归巢能力。如JAK-2磷酸化降低所示,CXCR4信号的干扰可能导致CAD患者EPC的功能受损。刺激CXCR4信号可能改善EPC的功能特性,并可能挽救CAD患者来源的EPC受损的新生血管形成能力。

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