Endothelial Damage, Vascular Bagging and Remodeling of the Microvascular Bed in Human Microangiopathy with Deep White Matter Lesions

White matter lesions (WMLs) are a common manifestation of small vessel disease (SVD) in the elderly population. They are associated with an enhanced risk of developing gait abnormalities, poor executive function, dementia, and stroke with high mortality. Hypoperfusion and the resulting endothelial damage are thought to contribute to the development of WMLs. The focus of the present study was the analysis of the microvascular bed in SVD patients with deep WMLs (DWMLs) by using double- and triple-label immunohistochemistry and immunofluorescence. Simultaneous visualization of collagen IV (COLL4)-positive membranes and the endothelial glycocalyx in thick sections allowed us to identify endothelial recession in different types of string vessels, and two new forms of small vessel/capillary pathology, which we called vascular bagging and ghost string vessels. Vascular bags were pouches and tubes that were attached to vessel walls and were formed by multiple layers of COLL4-positive membranes. Vascular bagging was most severe in the DWMLs of cases with pure SVD (no additional vascular brain injury, VBI). Quantification of vascular bagging, string vessels, and the density/size of CD68-positive cells further showed widespread pathological changes in the frontoparietal and/or temporal white matter in SVD, including pure SVD and SVD with VBI, as well as a significant effect of the covariate age. Plasma protein leakage into vascular bags and the white matter parenchyma pointed to endothelial damage and basement membrane permeability. Hypertrophic IBA1-positive microglial cells and CD68-positive macrophages were found in white matter areas covered with networks of ghost vessels in SVD, suggesting phagocytosis of remnants of string vessels. However, the overall vessel density was not altered in our SVD cohort, which might result from continuous replacement of vessels. Our findings support the view that SVD is a progressive and generalized disease process, in which endothelial damage and vascular bagging drive remodeling of the microvasculature.