Topper J N, Cai J, Qiu Y, Anderson K R, Xu Y Y, Deeds J D, Feeley R, Gimeno C J, Woolf E A, Tayber O, Mays G G, Sampson B A, Schoen F J, Gimbrone M A, Falb D
Vascular Research Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9314-9. doi: 10.1073/pnas.94.17.9314.
Vascular endothelium is an important transducer and integrator of both humoral and biomechanical stimuli within the cardiovascular system. Utilizing a differential display approach, we have identified two genes, Smad6 and Smad7, encoding members of the MAD-related family of molecules, selectively induced in cultured human vascular endothelial cells by steady laminar shear stress, a physiologic fluid mechanical stimulus. MAD-related proteins are a recently identified family of intracellular proteins that are thought to be essential components in the signaling pathways of the serine/threonine kinase receptors of the transforming growth factor beta superfamily. Smad6 and Smad7 possess unique structural features (compared with previously described MADs), and they can physically interact with each other, and, in the case of Smad6, with other known human MAD species, in endothelial cells. Transient expression of Smad6 or Smad7 in vascular endothelial cells inhibits the activation of a transfected reporter gene in response to both TGF-beta and fluid mechanical stimulation. Both Smad6 and Smad7 exhibit a selective pattern of expression in human vascular endothelium in vivo as detected by immunohistochemistry and in situ hybridization. Thus, Smad6 and Smad7 constitute a novel class of MAD-related proteins, termed vascular MADs, that are induced by fluid mechanical forces and can modulate gene expression in response to both humoral and biomechanical stimulation in vascular endothelium.
血管内皮是心血管系统中体液和生物力学刺激的重要传感器和整合器。利用差异显示方法，我们鉴定出两个基因，即Smad6和Smad7，它们编码MAD相关分子家族的成员，在培养的人血管内皮细胞中被生理性流体机械刺激——稳定层流切应力选择性诱导表达。MAD相关蛋白是最近鉴定出的一类细胞内蛋白，被认为是转化生长因子β超家族丝氨酸/苏氨酸激酶受体信号通路的重要组成部分。Smad6和Smad7具有独特的结构特征（与先前描述的MAD蛋白相比），它们可以相互物理作用，并且在血管内皮细胞中，Smad6还能与其他已知的人类MAD蛋白相互作用。在血管内皮细胞中瞬时表达Smad6或Smad7可抑制转染的报告基因对TGF-β和流体机械刺激的激活。通过免疫组织化学和原位杂交检测发现，Smad6和Smad7在体内人血管内皮中均呈现选择性表达模式。因此，Smad6和Smad7构成了一类新型的MAD相关蛋白，称为血管MAD蛋白，它们由流体机械力诱导产生，并能在血管内皮中响应体液和生物力学刺激来调节基因表达。
