Jiang Zhihua, Tao Ming, Omalley Kerri A, Wang Danlu, Ozaki C Keith, Berceli Scott A
Malcom Randall Veterans Affairs Medical Center, University of Florida College of Medicine, Gainesville, Florida, USA.
Am J Physiol Heart Circ Physiol. 2009 Oct;297(4):H1200-7. doi: 10.1152/ajpheart.00268.2009. Epub 2009 Jul 17.
In weeks to months following implantation, neointimal hyperplasia (NIH) in vein grafts (VGs) transitions from a cellularized to a decellularized phenotype. The inhibition of early cellular proliferation failed to improve long-term VG patency. We have previously demonstrated that transforming growth factor-beta(1) (TGF-beta(1))/connective tissue growth factor (CTGF) pathways mediate a conversion of fibroblasts to myofibroblasts in the early VG (<2 wk). We hypothesize that these similar pathways drive fibrosis observed in the late VG lesion. Within rabbit VGs, real-time RT-PCR, Western blot analysis, ELISA, and immunohistochemistry were used to examine TGF-beta/CTGF pathways in late (1-6 mo) NIH. All VGs exhibited a steady NIH growth (P = 0.006) with significant reduction in cellularity (P = 0.01) over time. Substantial TGF-beta profibrotic activities, as evidenced by enhanced TGF-beta(1) activation, TGF-beta receptor types I (activin receptor-like kinase 5)-to-II receptor ratio, SMAD2/3 phosphorylation, and CTGF production, persisted throughout the observation period. An increased matrix synthesis was accompanied by a temporal reduction of matrix metalloproteinase-2 (P = 0.001) and -9 (P < 0.001) activity. VG NIH is characterized by a conversion from a proproliferative to a profibrotic morphology. An enhanced signaling via TGF-beta/CTGF coupled with reduced matrix metalloproteinase activities promotes progressive fibrotic NIH expansion. The modulation of late TGF-beta/CTGF signaling may offer a novel therapeutic strategy to improve the long-term VG durability.
在植入后的数周乃至数月内，静脉移植物（VG）中的新生内膜增生（NIH）从细胞化表型转变为去细胞化表型。抑制早期细胞增殖并不能改善静脉移植物的长期通畅率。我们之前已经证明，转化生长因子-β(1)（TGF-β(1)）/结缔组织生长因子（CTGF）通路在早期静脉移植物（<2周）中介导成纤维细胞向肌成纤维细胞的转化。我们假设这些相似的通路驱动了晚期静脉移植物病变中观察到的纤维化。在兔静脉移植物中，采用实时逆转录聚合酶链反应（RT-PCR）、蛋白质印迹分析、酶联免疫吸附测定（ELISA）和免疫组织化学方法检测晚期（1 - 6个月）新生内膜增生中的TGF-β/CTGF通路。所有静脉移植物的新生内膜增生均持续稳定生长（P = 0.006），且随着时间推移细胞数量显著减少（P = 0.01）。在整个观察期内，TGF-β的促纤维化活性持续存在，表现为TGF-β(1)激活增强、I型（激活素受体样激酶5）与II型TGF-β受体比例增加、SMAD2/3磷酸化以及CTGF产生增加。基质合成增加的同时，基质金属蛋白酶-2（P = 0.001）和-9（P < 0.001）的活性随时间下降。静脉移植物新生内膜增生的特征是从增殖性形态转变为纤维化形态。通过TGF-β/CTGF增强的信号传导以及基质金属蛋白酶活性降低促进了纤维化新生内膜的渐进性扩展。调节晚期TGF-β/CTGF信号传导可能为改善静脉移植物的长期耐用性提供一种新的治疗策略。
