Interstitial flow promotes vascular fibroblast, myofibroblast, and smooth muscle cell motility in 3-D collagen I via upregulation of MMP-1
Interstitial flow promotes vascular fibroblast, myofibroblast, and smooth muscle cell motility in 3-D collagen I via upregulation of MMP-1
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DOI：
10.1152/ajpheart.00369.2009
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发表时间：
2009-10-01
影响因子：
4.8
通讯作者：
Tarbell, John M.
中科院分区：
文献类型：
--
作者：
Shi, Zhong-Dong;Ji, Xin-Ying;Tarbell, John M.
石志东，季晓云，卡子H，塔贝尔JM。间质血流通过上调基质金属蛋白酶-1促进血管成纤维细胞、肌成纤维细胞和3-D I型胶原中的平滑肌细胞的运动。Am J Physiol心圈Physiol 297：H1225-H1234,2009。2009年5月22日首次出版；doi：10.1152/ajpheart.00369.2009。-新生内膜形成通常发生在内皮受损和跨壁间质血流增加的区域。血管平滑肌细胞(SMCs)和成纤维细胞/肌成纤维细胞(FBS/MFBs)通过从中膜和外膜迁移到损伤部位而导致内膜增厚。在本研究中，首次在体外三维系统中研究了间质血流对SMC和FB/MFB迁移的直接影响。用I型胶原凝胶模拟大鼠主动脉SMC和FBS/MFBs的三维细胞外基质(ECM)。暴露于1cmH(2)O压差(切应力，相当于0.05dyn/cm(2)；流速，相当于0.5µm/S；达西通透性，相当于10(-11)cm(2))诱导的间质流动，显著增强细胞的运动能力。基质金属蛋白酶(MMPs)抑制剂(GM-6001)可阻断血流诱导的移行增强，提示这种增强的运动依赖于MMPs。MMP1表达上调在血流增强运动中起关键作用，沉默MMP1基因表达进一步证实了这一点。较长时间的高流量暴露抑制了迁移细胞的数量，尽管基质金属蛋白酶-1基因的表达仍然很高。这种抑制是流动诱导的金属蛋白酶组织抑制因子-1上调和增加细胞凋亡和坏死性死亡的结果。间质流动对任何细胞类型的I型胶原凝胶中的基质金属蛋白酶-2基因的表达或活性均无影响。我们的发现揭示了血管SMC和FBS/MFBs在间质血流增加的血管损伤区域促进内膜增厚的机制。
Shi ZD, Ji XY, Qazi H, Tarbell JM. Interstitial flow promotes vascular fibroblast, myofibroblast, and smooth muscle cell motility in 3-D collagen I via upregulation of MMP-1. Am J Physiol Heart Circ Physiol 297: H1225-H1234, 2009. First published May 22, 2009; doi: 10.1152/ajpheart.00369.2009.-Neointima formation often occurs in regions where the endothelium has been damaged and the transmural interstitial flow is elevated. Vascular smooth muscle cells (SMCs) and fibroblasts/myofibroblasts (FBs/MFBs) contribute to intimal thickening by migrating from the media and adventitia into the site of injury. In this study, for the first time, the direct effects of interstitial flow on SMC and FB/MFB migration were investigated in an in vitro three-dimensional system. Collagen I gels were used to mimic three-dimensional extracellular matrix (ECM) for rat aortic SMCs and FBs/MFBs. Exposure to interstitial flow induced by 1 cmH(2)O pressure differential (shear stress, similar to 0.05 dyn/cm(2); flow velocity, similar to 0.5 mu m/s; and Darcy permeability, similar to 10(-11) cm(2)) substantially enhanced cell motility. Matrix metalloproteinase (MMP) inhibitor (GM-6001) abolished flow-induced migration augmentation, which suggested that the enhanced motility was MMP dependent. The upregulation of MMP-1 played a critical role for the flow-enhanced motility, which was further confirmed by silencing MMP-1 gene expression. Longer exposures to higher flows suppressed the number of migrated cells, although MMP-1 gene expression remained high. This suppression was a result of both flow-induced tissue inhibitor of metalloproteinase-1 upregulation and increased apoptotic and necrotic cell death. Interstitial flow did not affect MMP-2 gene expression or activity in the collagen I gel for any cell type. Our findings shed light on the mechanism by which vascular SMCs and FBs/MFBs contribute to intimal thickening in regions of vascular injury where interstitial flow is elevated.