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.
Highlights
Small vessel disease (SVD) of the brain is a common cause of stroke and vascular dementia and plays an important role as a cofactor for Alzheimer’s dementia and Parkinson’s disease [1,2,3,4,5,6,7,8,9]
We found similar patterns of deposition of Von Willebrand factor (vWF) in human cerebral small vessels in small vessel vascular dementia, multiple infarct dementia, sickle cell disease, and post-radiation vasculopathy (Figure 1)
The transmural distribution of vWF protein in a wide range of cerebral SVD is similar to what we observed in CADASIL
Summary
Small vessel disease (SVD) of the brain is a common cause of stroke and vascular dementia and plays an important role as a cofactor for Alzheimer’s dementia and Parkinson’s disease [1,2,3,4,5,6,7,8,9]. Vascular smooth muscle cell disease has emerged as a key feature of SVD. Genetic analysis has clearly implicated smooth muscle disease in familial SVD. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common inherited cause of vascular dementia [12], is caused by mutations in NOTCH3 [13], a gene preferentially expressed in vascular smooth muscle [14,15]. Mutations in COL4A1, a gene encoding the main component of smooth muscle basement membranes, causes SVD in families with inherited leukoencephalopathy [16,17,18]. Pathways by which mutant NOTCH3 and COL4A1 lead to smooth muscle dysfunction and SVD are under active investigation
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