MT1-matrix metalloproteinase directs arterial wall invasion and neointima formation by vascular smooth muscle cells.
MT1-matrix metalloproteinase directs arterial wall invasion and neointima formation by vascular smooth muscle cells.
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DOI：
10.1084/jem.20050607
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发表时间：
2005-09-05
期刊：
影响因子：
--
通讯作者：
Weiss SJ
中科院分区：
文献类型：
--
作者：
Filippov S;Koenig GC;Chun TH;Hotary KB;Ota I;Bugge TH;Roberts JD;Fay WP;Birkedal-Hansen H;Holmbeck K;Sabeh F;Allen ED;Weiss SJ
在病理性血管重塑过程中，血管平滑肌细胞（VSMCs）嵌入动脉壁富含胶原的基质中，动员未表征的蛋白水解系统浸润内皮下空间并产生新生内膜病变。尽管VSMC衍生的丝氨酸蛋白酶、纤溶酶原激活剂和纤溶酶原、半胱氨酸蛋白酶、组织蛋白酶L、S和K以及基质金属蛋白酶MMP-2和MMP-9各自在体外和体内与病理性基质重塑状态相关，这些或其他蛋白酶在允许VSMCs通过三维（3-D）交叉-连接的动脉壁细胞外基质仍然不确定。在此，我们证明，血管平滑肌细胞蛋白水解重塑和侵入胶原屏障独立的纤溶酶，组织蛋白酶L，S，或K，MMP-2，或MMP-9。相反，我们确定膜锚定的基质金属蛋白酶，MT 1-MMP，作为关键的细胞周围的胶原蛋白溶解，控制的能力VSMCs降解和渗透3-D间质胶原蛋白的障碍，包括动脉壁。此外，蛋白酶的基因缺失使小鼠在体内具有针对新生内膜增生和管腔狭窄的保护状态。这些研究表明，针对MT 1-MMP设计的治疗性干预可以证明在与血管壁细胞外基质的破坏性重塑相关的一系列人类血管疾病状态中是有益的。
During pathologic vessel remodeling, vascular smooth muscle cells (VSMCs) embedded within the collagen-rich matrix of the artery wall mobilize uncharacterized proteolytic systems to infiltrate the subendothelial space and generate neointimal lesions. Although the VSMC-derived serine proteinases, plasminogen activator and plasminogen, the cysteine proteinases, cathepsins L, S, and K, and the matrix metalloproteinases MMP-2 and MMP-9 have each been linked to pathologic matrix-remodeling states in vitro and in vivo, the role that these or other proteinases play in allowing VSMCs to negotiate the three-dimensional (3-D) cross-linked extracellular matrix of the arterial wall remains undefined. Herein, we demonstrate that VSMCs proteolytically remodel and invade collagenous barriers independently of plasmin, cathepsins L, S, or K, MMP-2, or MMP-9. Instead, we identify the membrane-anchored matrix metalloproteinase, MT1-MMP, as the key pericellular collagenolysin that controls the ability of VSMCs to degrade and infiltrate 3-D barriers of interstitial collagen, including the arterial wall. Furthermore, genetic deletion of the proteinase affords mice with a protected status against neointimal hyperplasia and lumen narrowing in vivo. These studies suggest that therapeutic interventions designed to target MT1-MMP could prove beneficial in a range of human vascular disease states associated with the destructive remodeling of the vessel wall extracellular matrix.
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影响因子：
20.1
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