Basement membrane remodeling with fibroblast activation and cystatin C aggregation in cerebral vessels of hereditary cystatin C amyloid angiopathy.

Hereditary cystatin C amyloid angiopathy (HCCAA) is a familial form of cerebral amyloid angiopathy (CAA), a progressive disease that causes recurrent, often severe intracerebral hemorrhages and premature death in young adults. It is caused by a mutation in the CST3 gene that results in production of an aggregation-prone cystatin C protein. Basement membrane (BM) remodeling is implicated in the disease in both cerebral vessels and the skin. Here, we examined relationships between BM remodeling, vascular cellular alterations, signaling-associated markers, and cystatin C aggregation in HCCAA brain tissue using immunohistochemical analyses of cystatin C, α-smooth muscle actin (α-SMA), vimentin, collagen IV (COL IV), fibronectin 1 (FN1), SMAD2/3, phosphorylated SMAD2/3 (pSMAD2/3), and WNT-1. BM remodeling was prominent, COL IV and FN1 immunoreactivity was markedly increased, consistent with BM thickening, with FN1 immunoreactivity ~ 71% higher in leptomeningeal arteries/arterioles in HCCAA compared with controls. COL IV was elevated across arteries, arterioles, veins, venules, and capillaries, including capillaries lacking detectable cystatin C. In leptomeningeal arteries/arterioles, COL IV was ~ 79% higher, while in parenchymal vessels (including capillaries and veins/venules) COL IV was ~ 45% higher. Vascular cellular organization was altered, with redistributed α-SMA– and vimentin-positive cells within the vessel wall. Immunoreactivity for SMAD2/3, pSMAD2/3, and WNT-1 was detected in residual vascular cells across vessel wall layers in HCCAA. Quantitative analyses showed that SMAD2/3, pSMAD2/3, and WNT-1 immunoreactivity was not significantly reduced compared with controls, despite reduced cellularity in affected vessels. Together, these data indicate that early BM remodeling with COL IV and FN1 accumulation, accompanied by altered vascular cellular organization may contribute to impaired perivascular drainage and create a permissive environment for cystatin C aggregation. Therapeutic strategies targeting matrix homeostasis and profibrotic stress responses may hold potential for limiting vascular amyloid accumulation in HCCAA.