Contribution of intramural von Willebrand factor (VWF) to cerebrovascular dysfunction in amyloidosis

About This Grant

Summary. Von Willebrand factor (VWF) is a protein produced in endothelial cells and megakaryocytes. It is best known for its roles in hemostasis and thrombosis; however, an emerging literature has recently linked VWF with development of demenAa. In clinical studies, elevated plasma level of VWF and reduced acAvity of its protease (ADAMTS13) were shown to correlate with increased prevalence and risk for demenAa. In addiAon, elevated VWF is found in cerebrospinal fluid (CSF) of paAents with certain subtypes of Alzheimer’s disease, parAcularly those with vascular dysfuncAon. Normally, VWF within blood vessels is restricted to the endothelium and the immediately underlying basal lamina. However, the presence of VWF ‘deeper’ into the vessel wall (i.e. in the smooth muscle layer) is found in certain vascular pathologies and is referred to as “intramural VWF”. One contribuAng source of intramural VWF is thought to derive from the luminal side, resulAng from dysfuncAonal or damaged endothelial cells. But given that CSF bathes the outer surface of the leptomeningeal vasculature, elevated VWF in CSF may provide an addiAonal (perivascular) route by which VWF can reach smooth muscle cells (SMC) within the vascular wall. Our preliminary data demonstrate intramural VWF in cerebral vasculature in condiAons of amyloidosis, including arterioles of paAents with confirmed cerebral amyloid angiopathy (CAA) and in leptomeningeal arteries of Tg2576 mice (mouse model of amyloidosis). To define the funcAonal roles of intramural VWF, we performed experiments to increase and decrease perivascular VWF. We showed that perivascular VWF promotes abnormal vascular morphology and potenAates mechanisms of vascular remodeling, whereas VWF depleAon aZenuates vascular remodeling, specifically by reducing SMC proliferaAon. In separate experimental approaches, we showed that VWF promotes increased SMC migraAon and transcripAonal changes consistent with a more proliferaAve SMC phenotype. We will now test the overall hypothesis that intramural VWF amplifies pathological remodeling of leptomeningeal arteries in condiAons of amyloidosis, thereby contribuAng to cerebrovascular dysfuncAon, the development of CAA, and worsening of brain pathology. Aim 1 will define how VWF modifies cerebral smooth muscle funcAon and phenotype in the absence and presence of amyloidosis. MechanisAc studies will be performed with human brain SMC and validated in human Assues and a mouse model of amyloidosis (Tg2576). Aim 2 will test the hypothesis that intramural VWF impairs cerebrovascular funcAon and accelerates the development of CAA in the leptomeningeal vasculature. Studies will be performed in Tg2576 mice, which develop leptomeningeal CAA. Aim 3 will determine if reducing intramural VWF in Tg2576 mice can preserve or rescue cerebrovascular funcAon in different stages of vascular Ab pathology. CompleAon of these studies will define the role of intramural VWF in potenAaAng amyloid-driven cerebrovascular pathology and determine the potenAal of targeAng these VWF-mediated mechanisms as a means to reduce cerebrovascular dysfuncAon and slow progression of Alzheimer’s Disease and Alzheimer’s Disease Related DemenAas (AD/ADRD).