The role of urokinase plasminogen activator and plasmin activator inhibitor-1 on vein wall remodeling in experimental deep vein thrombosis.
The role of urokinase plasminogen activator and plasmin activator inhibitor-1 on vein wall remodeling in experimental deep vein thrombosis.
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DOI：
10.1016/j.jvs.2012.02.054
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发表时间：
2012-10
影响因子：
4.3
通讯作者：
Henke, Peter K.
中科院分区：
文献类型：
--
作者：
Baldwin, Joe F.;Sood, Vikram;Elfline, Megan A.;Luke, Cathy E.;Dewyer, Nicholas A.;Diaz, Jose A.;Myers, Dan D.;Wakefield, Thomas;Henke, Peter K.
深静脉血栓形成(DVT)的消退会引发炎症反应，导致血管壁损伤和瘢痕形成。尿激酶-纤溶酶原激活物(UPA)及其抑制物纤溶酶原激活物抑制物-1(PAI-1)是纤溶系统的组成部分，对室性心动过速的解决至关重要。这项研究确定了当暴露于纤溶酶活性增加和减少时的静脉壁反应。用uPA−/−或PAI-1−/−结扎小鼠下腔静脉模型及其遗传野生型(分别为B6/SvEv和C57/BL6)造成血栓形成，分别于第8天和第21天取材。组织学检测采用实时荧光定量聚合酶链式反应、酶联免疫吸附试验、基质金属蛋白酶-2和9活性检测、血管壁胶原蛋白表达检测、血管内皮细胞标志物(α-SMA)和血管内皮标志物(CD31)基因表达。P<；0.05被认为意义重大。血栓在8d和21d的uPA-1−/−组均显著大于WT组，而在8d和21d的−/−组显著小于WT组。相应地，与相应的WT血栓相比，uPA−/−的8d纤溶酶水平降低了一半，而PAI-1−/−的8d纤溶酶水平增加了3倍(P<；0.05，N=5-6)。与WT组相比，PAI-1−/−组小鼠血管内皮细胞CD31在8d时升高2倍，而在21d时降低2.5倍(P=0.02，N=5-6)，提示血管内皮细胞保存较差。静脉壁VSMC基因表达显示，第8天和第21天PAI-1−/−小鼠的αSMA表达分别是WT小鼠的2.3和3.8倍(P<；0.05，N=5-7)，αSMA(+)细胞增加1.8倍(N=3-5，P≤.05)。PAI-1−/−小鼠MMP2和MMP9活性与WT小鼠相比无显著差异，而21d WT小鼠MMP9活性是21DuPA−/−小鼠的5.4倍(P=0.03，N=5)。最后，在PAI-1−/−下腔静脉移植组，第8天的胶原含量是WT组的~2倍(P=0.03，N=6)，而在uPA-1−/−小鼠中没有观察到差异。在静脉性深静脉血栓形成中，纤溶酶活性对血栓的消退至关重要。不同的静脉壁反应随着纤溶酶活性的增强或丧失而发生，尽管VT较小，但较大的静脉壁纤维化与PAI-1的缺乏有关。
Deep vein thrombosis (DVT) resolution instigates an inflammatory response, resulting in vessel wall damage and scarring. Urokinase-plasminogen activator (uPA) and its inhibitor, plasminogen activator inhibitor-1 (PAI-1), are integral components of the fibrinolytic system, essential for VT resolution. This study determined the vein wall response when exposed to increased and decreased plasmin activity. A mouse inferior vena cava (IVC) ligation model in uPA −/− or PAI-1 −/− and their genetic wild types (B6/SvEv and C57/BL6, respectively) was used to create stasis thrombi, with tissue harvest at either 8 or 21d. Tissue analysis included gene expression of vascular smooth muscle cells (alpha SMA [αSMA], SM22) and endothelial marker (CD31), by real time PCR, ELISA, matrix metalloproteinase (MMP) -2 and 9 activity by zymography and vein wall collagen by picrosirius red histological analysis. A P < .05 was considered significant. Thrombi were significantly larger in both 8d and 21d uPA −/− as compared to WT, and were significantly smaller in both 8 and 21d PAI-1 −/− as compared to WT. Correspondingly, 8d plasmin levels were reduced in half in uPA −/− and increased 3 fold in PAI-1 −/− when compared to respective WT thrombi (P < .05, N = 5 – 6). The endothelial marker CD31 was elevated 2 fold in PAI-1 −/− mice at 8d, but reduced 2.5 fold at 21d in uPA −/− as compared with WT (P = .02, N = 5 – 6), suggesting less endothelial preservation. Vein wall VSMC gene expression showed that 8d and 21d PAI-1 −/− mice had 2.3 and 3.8 fold more SM22 and 1.8 and 2.3 fold more αSMA expression than respective WT (P < .05, N = 5 – 7), as well as 1.8 fold increased αSMA (+) cells (N = 3 – 5, P ≤ .05). No significant difference in MMP2 or 9 activity was found in the PAI-1 −/− mice compared with WT, while 5.4 fold more MMP9 was present in 21d WT than 21d uPA −/− (P = .03, N = 5). Lastly, collagen was ~2 fold greater at 8d in PAI-1 −/− IVC as compared to WT (P = .03, N = 6) with no differences observed in uPA −/− mice. In stasis DVT, plasmin activity is critical for thrombus resolution. Divergent vein wall responses occur with gain or loss of plasmin activity, and despite smaller VT, greater vein wall fibrosis was associated with lack of PAI-1.
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DOI：
10.1161/01.atv.0000042231.04318.e6
发表时间：
2002-12-01
影响因子：
8.7
作者：
de Waard, V;Arkenbout, EK;Pannekoek, H
通讯作者：
Pannekoek, H
影响因子：
15.9
作者：
Flick, Matthew J.;LaJeunesse, Christine M.;Degen, Jay L.
通讯作者：
Degen, Jay L.
影响因子：
2.9
作者：
Cuttle, L;Nataatmadja, M;Hayes, MT
通讯作者：
Hayes, MT
影响因子：
20.1
作者：
Moriwaki, H;Stempien-Otero, A;Dichek, DA
通讯作者：
Dichek, DA
影响因子：
2.2
作者：
Dewyer, Nicholas A.;Sood, Vikram;Henke, Peter K.
通讯作者：
Henke, Peter K.