Targeting intramural von Willebrand factor (VWF) to improve vasomotor function, enhance brain parenchymal clearance, & delay development of cerebral amyloid angiopathy (CAA) in conditions of amyloid

点击翻译按钮获取中文摘要

SUMMARY. The brain vasculature contributes to the vital clearance of Ab and other solutes from brain interstitial fluid (ISF). The following proposal examines the pathological role of von Willebrand factor (VWF) within the wall of leptomeningeal arteries and arterioles, with particular focus on its potential to impair cerebrovascular function and vascular-mediated clearance in conditions of amyloidosis. VWF is expressed exclusively in endothelial cells and platelets and is widely recognized for its role in hemostasis and thrombosis. The presence of extracellular VWF in blood vessels is normally confined to the luminal endothelial surface and immediate sub-endothelial matrix. However, in certain pathological states, VWF can be found within the vascular wall (i.e. intramural VWF) where it promotes smooth muscle proliferation and wall thickening. Importantly, we and others have shown that VWF deletion profoundly prevents this vascular remodeling. Our preliminary data now expand the role of intramural VWF to conditions of AD and CAA. We show the presence of VWF within the smooth muscle region of cerebral arteries and arterioles from human AD and CAA patients and in leptomeningeal arteries (LMA) from mouse models of amyloidosis. We further show that Ab peptides promote increased VWF expression in human brain endothelial cells, supporting a contributory role for amyloidosis in VWF accumulation in the vessel wall. Based on these findings, we propose the overall hypothesis that Ab contributes to increased basolateral endothelial release of VWF, where it triggers smooth muscle proliferation and subsequent wall thickening with narrowing of leptomeningeal arteries and cortical arterioles. We further propose that the consequences of intramural VWF include cerebrovascular dysfunction, impaired brain clearance of Ab peptides, and the acceleration of cerebral artery angiopathy (CAA) and related functional consequences. We propose studies to a) define the mechanisms by which intramural VWF leads to pathological LMA remodeling and impaired Ab clearance and b) evaluate the novel strategy of reducing intramural VWF to mitigate vascular-related pathology in amyloidosis. In Aim 1, we will test the hypothesis that Ab contributes to increased basolateral endothelial release of VWF, where it triggers smooth muscle proliferation and subsequent wall thickening with narrowing of LMAs and cortical arterioles. We will use a combination of human cell culture studies and in vivo studies in TgAPP mouse models following selective VWF knockdown in brain endothelium. In Aim 2, we will test the hypothesis that reduction of brain endothelial VWF will result in increased Ab clearance by improving transendothelial and paravascular clearance mechanisms. We will evaluate selective knockdown of VWF in brain endothelium on different components of ISF flow and Ab clearance in TgAPP mice. In Aim 3, we will test the hypothesis that knockdown of brain endothelial VWF will prevent or stabilize vasomotor dysfunction and reduce vascular-driven pathology in conditions of amyloidosis. For this proof-of-concept study, we will employ behavior testing, in vivo measures of cerebrovascular function, and brain histological analyses to determine the beneficial effect of VWF knockdown in TgAPP mouse models. If successful, these studies will establish the pathological role of VWF located within the vascular wall and thus provide the initial experimental support for therapeutically targeting intramural VWF in conditions of amyloidosis.