Yau Terrence M, Li Guangming, Zhang Yaoguang, Weisel Richard D, Mickle Donald A G, Li Ren-Ke
Division of Cardiovascular Surgery, Toronto General Hospital, University Health Network, University of Toronto, Heart & Stroke Foundation, Richard Lewar Centre of Excellence, Toronto, Ontario, Canada.
Ann Thorac Surg. 2005 Jun;79(6):2056-63. doi: 10.1016/j.athoracsur.2004.10.066.
We have previously reported that transplantation of vascular endothelial growth factor transfected cells into myocardial scar enhances angiogenesis. We evaluated the effect of transplanted cell type, time, and region of the heart on expression of the vascular endothelial growth factor receptors fms-like tyrosine kinase-1 (flt-1) and fetal liver kinase-1 (flk-1).
Lewis rats underwent myocardial cryoinjury 3 weeks before transplantation with heart cells (a mixed culture of cardiomyocytes, smooth muscle cells, endothelial cells, and fibroblasts), vascular endothelial growth factor transfected heart cells, skeletal myoblasts, vascular endothelial growth factor transfected skeletal myoblasts, or medium (controls) (N = 13 each). Flt-1 and flk-1 expression in the scar, border zone, and normal myocardium were evaluated at 3 days and 1, 2, and 4 weeks by quantitative polymerase chain reaction. Transplanted cells, vascular endothelial growth factor, flt-1, and flk-1 were identified by immunohistology.
Flt-1 and flk-1 levels were low in all areas of control hearts. Upregulation of flt-1 and flk-1 after cell transplantation occurred primarily in host cells in the border zone rather than the scar (zone, p < 0.0001). Flt-1 and flk-1 expression was doubled by heart cells and skeletal myoblasts and increased eightfold by vascular endothelial growth factor transfected heart cells and skeletal myoblasts (group, p < 0.0001). Flk-1 expression peaked at 1 week, whereas flt-1 peaked at 2 weeks (time, p < 0.0001).
Flk-1 and flt-1 upregulation may mediate the angiogenic effect of cell transplantation and are augmented by vascular endothelial growth factor transgene expression, perhaps through a paracrine effect. Optimizing the angiogenic response to cell transplantation may maximize the benefit of cell transplantation strategies.
我们之前报道过，将血管内皮生长因子转染细胞移植到心肌瘢痕中可促进血管生成。我们评估了移植细胞类型、时间以及心脏区域对血管内皮生长因子受体fms样酪氨酸激酶-1（flt-1）和胎儿肝激酶-1（flk-1）表达的影响。
Lewis大鼠在移植前3周接受心肌冷冻损伤，移植的细胞包括心脏细胞（心肌细胞、平滑肌细胞、内皮细胞和成纤维细胞的混合培养物）、血管内皮生长因子转染的心脏细胞、骨骼肌成肌细胞、血管内皮生长因子转染的骨骼肌成肌细胞或培养基（对照组）（每组N = 13）。在第3天以及第1、2和4周，通过定量聚合酶链反应评估瘢痕、边缘区和正常心肌中flt-1和flk-1的表达。通过免疫组织学鉴定移植细胞、血管内皮生长因子、flt-1和flk-1。
对照心脏所有区域的flt-1和flk-1水平均较低。细胞移植后flt-1和flk-1的上调主要发生在边缘区的宿主细胞而非瘢痕中（区域，p < 0.0001）。心脏细胞和骨骼肌成肌细胞使flt-1和flk-1表达增加一倍，血管内皮生长因子转染的心脏细胞和骨骼肌成肌细胞使其增加八倍（组，p < 0.0001）。flk-1表达在第1周达到峰值，而flt-1在第2周达到峰值（时间，p < 0.0001）。
Flk-1和flt-1的上调可能介导细胞移植的血管生成作用，并且血管内皮生长因子转基因表达可增强这种作用，可能是通过旁分泌效应。优化对细胞移植的血管生成反应可能会使细胞移植策略的益处最大化。
