Otsuka Goro, Agah Ramtin, Frutkin Andrew D, Wight Thomas N, Dichek David A
Department of Medicine, University of Washington, Seattle, WA 98195-7710, USA.
Arterioscler Thromb Vasc Biol. 2006 Apr;26(4):737-43. doi: 10.1161/01.ATV.0000201087.23877.e1. Epub 2005 Dec 22.
The mechanisms through which transforming growth factor (TGF)-beta1 promotes intimal growth, and the pathways through which TGF-beta1 expression is regulated in the artery wall, are incompletely understood. We used a mouse model to investigate mechanisms of TGF-beta1-induced intimal growth.
Adenovirus-mediated overexpression of TGF-beta1 in uninjured carotid arteries of wild-type mice induced formation of a cellular and matrix-rich intima. Intimal growth appeared primarily due to cell migration and matrix accumulation, with only a negligible contribution from cell proliferation. Overexpression of TGF-beta1 also stimulated expression of plasminogen activator inhibitor type 1 (plasminogen activator inhibitor [PAI]-1) in the artery wall. To test the hypothesis that PAI-1 is a critical downstream mediator of TGF-beta1-induced intimal growth, we transduced carotid arteries of PAI-1-deficient (Serpine1(-/-)) mice with the TGF-beta1-expressing vector. Overexpression of TGF-beta1 in Serpine1(-/-) arteries did not increase intimal growth, matrix accumulation, cell migration, or proliferation. Moreover, TGF-beta1-transduced arteries of Serpine1(-/-) mice secreted 6- to 10-fold more TGF-beta1 than did arteries of wild-type mice that were infused with the same concentration of the TGF-beta1-expressing vector.
PAI-1 is both a critical mediator of TGF-beta1-induced intimal growth and a key negative regulator of TGF-beta1 expression in the artery wall.
转化生长因子（TGF）-β1促进内膜生长的机制以及TGF-β1在动脉壁中表达的调控途径尚未完全明确。我们使用小鼠模型来研究TGF-β1诱导内膜生长的机制。
腺病毒介导的TGF-β1在野生型小鼠未损伤的颈动脉中过表达，可诱导富含细胞和基质的内膜形成。内膜生长主要源于细胞迁移和基质积累，细胞增殖的作用可忽略不计。TGF-β1的过表达还刺激了动脉壁中纤溶酶原激活物抑制剂1（纤溶酶原激活物抑制剂[PAI]-1）的表达。为了验证PAI-1是TGF-β1诱导内膜生长的关键下游介质这一假设，我们用表达TGF-β1的载体转导PAI-1缺陷（Serpine1(-/-)）小鼠的颈动脉。TGF-β1在Serpine1(-/-)动脉中的过表达并未增加内膜生长、基质积累、细胞迁移或增殖。此外，转导了TGF-β1的Serpine1(-/-)小鼠动脉分泌的TGF-β1比输注相同浓度表达TGF-β1载体的野生型小鼠动脉多6至10倍。
PAI-1既是TGF-β1诱导内膜生长的关键介质，也是动脉壁中TGF-β1表达的关键负调节因子。
