Role and mechanism of tissue plasminogen activator in venous wall fibrosis remodeling after deep venous thrombosis via the glycogen synthase kinase-3 beta signaling pathway.
Role and mechanism of tissue plasminogen activator in venous wall fibrosis remodeling after deep venous thrombosis via the glycogen synthase kinase-3 beta signaling pathway.
复制标题
组织纤溶酶原激活剂通过糖原合酶激酶-3β信号通路在深静脉血栓形成后静脉壁纤维化重塑中的作用和机制。
DOI：
10.1016/j.jss.2013.03.100
复制
发表时间：
2013
期刊：
影响因子：
--
通讯作者：
M. Jiang
中科院分区：
文献类型：
--
作者：
M. Yin;Shuo Tian;Xin;Ying Huang;M. Jiang
背景深静脉血栓形成(DVT)可导致与纤维化和细胞外基质代谢相关的静脉壁损伤。血管平滑肌细胞(VSMCs)的激活和表型转换被认为是致病过程中的重要贡献因素。本研究探讨组织型纤溶酶原激活剂(TPA)对VSMCs表型转换和胶原沉积的影响及其相关信号转导途径。材料与方法结扎股静脉建立DVT模型。用携带带有增强型绿色荧光蛋白(EGFP)标签的大鼠重组tPA基因的载体(AdtPA-EGFP)转染VSMC。比较AdtPA-EGFP转染组、空载体(AdNull-EGFP)转染组和磷酸盐缓冲液生理盐水灌注组的体内纤维化变化、I型胶原表达、中膜细胞数和内膜厚度评分。TPA在体外诱导VSMCs表型转换和胶原沉积。结果在AdtPA-EGFP血瘀型DVT模型中，早期静脉壁胶原溶解和沉积更为明显。组织学检查显示静脉壁I型胶原蛋白表达、中层细胞数、内膜厚度积分显著增加(P<；0.05)。在原代培养的VSMC中，tPA持续刺激可诱导I型胶原表达上调，并触发细胞外信号调节蛋白1/2(ERK1/2)、糖原合成酶-3(GSK3)-β磷酸化和细胞周期蛋白D1诱导等一系列信号转导事件。阻断磷脂酰肌醇3-激酶-Akt和ERK1/2的激活抑制tPA诱导的GSK3β的磷酸化、细胞周期蛋白D1的表达和I型胶原的沉积。结论纤溶酶原激活剂是一种促进VSMC表型转换和胶原沉积的促纤维化因子。组织型纤溶酶原激活剂可能通过激活Akt和ERK1/2通路，抑制GSK3β活性，从而促进VSMC合成表型的转换，导致血管损伤的重塑。
BackgroundDeep venous thrombosis (DVT) confers vein wall injury associated with fibrosis and extracellular matrix turnover. The activation of vascular smooth muscle cells (VSMCs) and phenotypic switching are postulated to be the significant contributing factors in the evolution of the pathogenic processes. This study investigated the effect of tissue plasminogen activator (tPA) on the phenotypic switching and collagen deposition of VSMCs, as well as related signaling pathway that leads to this activation.Materials and methodsThe model of stasis-induced DVT was established by ligation of the femoral vein. VSMCs transfected with the plasmid vector carrying a rat recombinant tPA gene with an enhanced green fluorescent protein (EGFP) tag (AdtPA-EGFP). Fibrotic change, expression of collagen type I, the cell number of media, and intimal thickness score were evaluated; the comparisons were made among the AdtPA-EGFP–transfected group, an empty vector (AdNull-EGFP) transfected group, and a phosphate-buffered saline perfused groupin vivo. tPA induced VSMCs phenotypic switching and collagen depositionin vitro. The related signaling pathway molecules and the cell cycle progression were also investigated by western blot and flow cytometry.ResultsIn the AdtPA-EGFP stasis DVT model, early vein wall collagenolysis and deposition occurred more remarkable. Histological studies showed that the expression of vein wall collagen type I protein, cell number of media, and intimal thickness score was significantly increased (P< 0.05). In primary culture VSMCs, sustained stimulation with tPA induced collagen type I upregulation and triggered sequential signaling events involving Akt, extracellular signal–regulated kinases 1/2 (ERK1/2), glycogen synthase kinase-3 (GSK3)-β phosphorylation, and cyclin D1 induction. Blockade of phosphatidylinositol 3-kinase-Akt and ERK1/2 activation suppressed tPA-induced GSK3β phosphorylation, cyclin D1 expression, and the deposition of collagen type I.ConclusionstPA was a profibrotic factor that potentiated the phenotypic switching and the deposition of collagen in VSMC. The effect of tPA on VSMCs involved activation of Akt and ERK1/2 pathways and inhibition of GSK3β activity, which could promote a switch of the synthetic phenotype in VSMCs and lead to the remodeling of vascular injury.
DOI：
10.2353/ajpath.2009.080661
发表时间：
2009-02
期刊：
The American journal of pathology
影响因子：
--
作者：
Chen Zhang;J. An;D. Strickland;M. Yepes
通讯作者：
Chen Zhang;J. An;D. Strickland;M. Yepes
影响因子：
15.9
作者：
Hu, Kebin;Wu, Chuanyue;Liu, Youhua
通讯作者：
Liu, Youhua
影响因子：
6
作者：
Hao, Sha;Shen, Hongmei;Liu, Youhua
通讯作者：
Liu, Youhua