Von Willebrand factor inhibits mature smooth muscle gene expression through impairment of Notch signaling.
Von Willebrand factor inhibits mature smooth muscle gene expression through impairment of Notch signaling.
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DOI：
10.1371/journal.pone.0075808
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wang MM
中科院分区：
文献类型：
--
作者：
Meng H;Zhang X;Lee SJ;Wang MM
血管性血友病因子（vWF）是一种止血蛋白，通常由内皮细胞和血小板合成和储存，在血管疾病状态下已定位于内皮之外。以前的研究已经暗示vWF的潜在非止血功能，但其作用的信号转导机制目前尚不明确。我们提供的证据表明，vWF在脑小血管疾病（SVD）中突破内皮并以跨壁分布模式表达。为了确定vWF渗透到血管壁中的潜在分子后果，我们还测试了vWF是否损害关键平滑肌标志物基因的Notch调节。在使用Notch配体表达细胞刺激A7 R5细胞中的Notch的共培养系统中，vWF强烈抑制Notch途径和成熟平滑肌基因启动子的活化。在原代人脑血管平滑肌细胞中观察到类似的抑制作用。NOTCH 3的细胞内结构域的表达允许细胞绕过vWF的抑制作用。此外，vWF与所有四种哺乳动物Notch胞外域形成分子复合物，表明vWF作为Notch信号传导的细胞外抑制剂的新功能。总之，这些研究表明血管壁中的vWF是脑SVD的共同特征;此外，我们提供了一种合理的机制，非止血vWF可能在促进血管疾病中发挥新的作用。
Von Willebrand factor (vWF), a hemostatic protein normally synthesized and stored by endothelial cells and platelets, has been localized beyond the endothelium in vascular disease states. Previous studies have implicated potential non-hemostatic functions of vWF, but signaling mechanisms underlying its effects are currently undefined. We present evidence that vWF breaches the endothelium and is expressed in a transmural distribution pattern in cerebral small vessel disease (SVD). To determine the potential molecular consequences of vWF permeation into the vessel wall, we also tested whether vWF impairs Notch regulation of key smooth muscle marker genes. In a co-culture system using Notch ligand expressing cells to stimulate Notch in A7R5 cells, vWF strongly inhibited both the Notch pathway and the activation of mature smooth muscle gene promoters. Similar repressive effects were observed in primary human cerebral vascular smooth muscle cells. Expression of the intracellular domain of NOTCH3 allowed cells to bypass the inhibitory effects of vWF. Moreover, vWF forms molecular complexes with all four mammalian Notch ectodomains, suggesting a novel function of vWF as an extracellular inhibitor of Notch signaling. In sum, these studies demonstrate vWF in the vessel wall as a common feature of cerebral SVD; furthermore, we provide a plausible mechanism by which non-hemostatic vWF may play a novel role in the promotion of vascular disease.
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