Tang Y, Urs S, Boucher J, Bernaiche T, Venkatesh D, et al...

来自 : www.oalib.com/references/10729 发布时间：2021-03-24

ABSTRACT: 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.
J Biol Chem 285: 17556–17563.被如下文章引用:TITLE: Von Willebrand Factor Inhibits Mature Smooth Muscle Gene Expression through Impairment of Notch ...Tang Y, Urs S, Boucher J, Bernaiche T, Venkatesh D, et al. (2010) Notch and transforming growth factor-beta (TGFbeta) signaling pathways cooperatively regulate vascular smooth muscle cell differentiation. J Biol Chem 285: 17556–17563.Tang Y, Urs S, Boucher J, Bernaiche T, Venkatesh D, et al. (2010) Notch and transforming growth factor-beta (TGFbeta) signaling pathways cooperatively regulate vascular smooth muscle cell differentiation. J Biol Chem 285: 17556–17563.Tang Y, Urs S, Boucher J, Bernaiche T, Venkatesh D, et al. (2010) Notch and transforming growth factor