Cerebral small vessel disease is a form of age-related dysfunction in the smaller blood vessels of the brain, associated with damage to the white matter of the brain and the onset of dementia. It is thought that the increased blood pressure of hypertension and consequent physical stresses on blood vessel walls is the primary cause of small vessel disease, but here researchers provide evidence pointing towards specific forms of change in signaling generated by dysfunctional endothelial cells that form the blood-brain barrier in blood vessel walls. That signaling degrades some of the necessary supporting operations of cells in nearby brain tissue – a situation that sounds similar to the outcome of cellular senescence and the senescence-associated secretory phenotype, though that topic isn’t mentioned at all in this paper. This endothelial cell signaling occurs prior to other aspects of small vessel disease, though itself must still be secondary to the underlying molecular damage of aging in and around blood vessel cells: senescence, cross-linking, and so forth.
Cerebral small vessel disease (SVD) affects arterioles in the brain, increasing risk of stroke and causing symptoms of dementia. Magnetic resonance scans of SVD patients typically show white matter abnormalities, but we do not understand the mechanistic pathological link between blood vessels and white matter myelin damage. Hypertension is suggested as the cause of sporadic SVD, but a recent alternative hypothesis invokes dysfunction of the blood-brain barrier as the primary cause.
In a rat model of SVD, we show that endothelial cell (EC) dysfunction is the first change in development of the disease. Dysfunctional ECs secrete heat shock protein 90α, which blocks oligodendroglial differentiation, contributing to impaired myelination: vascular tight junctions of the blood-brain barrier were impaired in SVD, and dysfunctional endothelial cells prevented oligodendrocyte precursors from maturing into myelinating cells.
Treatment with EC-stabilizing drugs reversed these EC and oligodendroglial pathologies in the rat model. EC and oligodendroglial dysfunction were also observed in humans with early, asymptomatic SVD pathology. We identified a loss-of-function mutation in ATPase11B, which caused the EC dysfunction in the rat SVD model, and a single-nucleotide polymorphism in ATPase11B that was associated with white matter abnormalities in humans with SVD. We show that EC dysfunction is a cause of SVD white matter vulnerability and provide a therapeutic strategy to treat and reverse SVD in the rat model, which may also be of relevance to human SVD.