Endothelial dysfunction and cerebral small-vessel disease in brains of older people.

Abstract

Cerebral small vessel disease (SVD) affects deep penetrating arteries in subcortical white matter and deep grey nuclei, and is a frequent finding at autopsy in brains of older people. SVD is seen as fibrotic thickening of deep penetrating arteries (outer diameter <200 µm), with loss of mural cells and sparing of endothelial cells (Hainsworth et al. 2015). SVD is the underlying cause of most lacunar stroke events, silent focal infarcts and subcortical microbleeds, and is associated with diffuse white matter hyperintensities seen on T2-weighted MRI scans. Brain lesions due to SVD are a major cause of vascular contributions to cognitive impairment and dementia (VCID). In semi-quantitative neuropathological studies of human brain tissue we have examined vascular expression of diverse proteins related to endothelial dysfunction and SVD. We found the antithrombotic protein thrombomodulin localised to small artery endothelia, with more extensive expression in older people with SVD, relative to those without (p=0.012). The inflammation markers ICAM1 and IL-6 were rarely evident in endothelia, and appeared unrelated to SVD. The angiogenic receptor VEGFR2 was robustly expressed in vascular myocytes of small arteries of older people and also those with monogenic SVD (CADASIL), suggesting a role for VEGF signalling in small artery remodelling. The extent of VEGFR2 labelling increased with age (p=0.0026) but not with presence of SVD. The extent of vascular basement membrane collagen-IV, types α1-IV and α2-IV (encoded by COL4A1/COL4A2, genetically associated with SVD) in small arteries was negatively correlated with radiological SVD severity (Spearman's rho: -0.427, p=0.005). Neuropathological studies in human brain tissue yield valuable molecular data on SVD pathology. These are hypothesis-generating for testing of interventions in preclinical models, and future clinical trials. Reference: Hainsworth et al. 2015. Endothelial Cells and Human Cerebral Small Vessel Disease. Brain Pathol. 25;44.