Department of Cell Biology-Immunology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Atherosclerosis. 2010 Apr;209(2):393-402. doi: 10.1016/j.atherosclerosis.2009.10.020. Epub 2009 Oct 22.
Transplant vasculopathy consists of neointima formation in graft vasculature resulting from vascular smooth muscle cell recruitment and proliferation. Variation in the severity of vasculopathy has been demonstrated. Genetic predisposition is suggested as a putative cause of this variation, although cellular mechanisms are still unknown. Using a rat aorta transplant model we tested the hypothesis that kinetics of development of transplant vasculopathy are related to neointimal smooth muscle cell proliferative capacity and fibrocyte frequency, the latter being putative neointimal smooth muscle ancestral cells.
Aortic allografts were transplanted in Lewis and Brown Norway, as well as MHC-congenic Lewis.1N and Brown Norway.1L recipients. Severity of transplant vasculopathy was quantified 4, 8, 12 and 24 weeks after transplantation. Host-endothelial chimerism, as a reflection of vascular injury, was determined by specific immunofluorescence. Neointimal smooth muscle cell proliferative capacity was determined in vitro and in situ. Fibrocyte frequency and phenotype were determined after in vitro culture by cell counting, immunofluorescence and in situ zymography.
Compared to Lewis, Brown Norway recipients developed accelerated transplant vasculopathy which is dependent on the presence of Brown Norway non-MHC-encoded determinants. Accelerated transplant vasculopathy was associated with increased levels of host-endothelial chimerism and increased neointimal smooth muscle cell proliferation, the latter being accompanied by increased endothelial and smooth muscle cell-derived neuropilin-like protein mRNA expression. Moreover, accelerated transplant vasculopathy was associated with increased frequency of circulating gelatinase-expressing CD45(+)vimentin(+) fibrocytes.
Susceptibility for transplant vasculopathy appears to be genetically controlled and correlates with neointimal smooth muscle cell proliferative capacity and circulating fibrocyte frequency.
移植物血管病由血管平滑肌细胞募集和增殖导致移植物血管内的新生内膜形成组成。已经证明血管病的严重程度存在差异。遗传易感性被认为是这种差异的潜在原因，尽管细胞机制尚不清楚。我们使用大鼠主动脉移植模型检验了以下假设：移植血管病发展的动力学与新生内膜平滑肌细胞增殖能力和纤维母细胞频率有关，后者是假定的新生内膜平滑肌祖细胞。
将主动脉同种异体移植物移植到 Lewis 和 Brown Norway 大鼠，以及 MHC 同基因 Lewis.1N 和 Brown Norway.1L 受体中。在移植后 4、8、12 和 24 周时定量评估移植血管病的严重程度。宿主内皮嵌合率，作为血管损伤的反映，通过特异性免疫荧光法确定。体外和原位测定新生内膜平滑肌细胞增殖能力。纤维母细胞频率和表型通过细胞计数、免疫荧光和原位酶谱法在体外培养后确定。
与 Lewis 大鼠相比，Brown Norway 大鼠发展出加速的移植血管病，这依赖于 Brown Norway 非 MHC 编码决定因素的存在。加速的移植血管病与宿主内皮嵌合率增加和新生内膜平滑肌细胞增殖增加有关，后者伴随着内皮和平滑肌细胞衍生的神经纤毛样蛋白 mRNA 表达增加。此外，加速的移植血管病与循环中表达明胶酶的 CD45(+)波形蛋白(+)纤维母细胞频率增加有关。
移植血管病的易感性似乎受遗传控制，与新生内膜平滑肌细胞增殖能力和循环纤维母细胞频率相关。
