Cerebral small vessel disease: Pathological mechanisms and potential therapeutic targets

Abstract

Cerebral small vessel disease (CSVD) represents a diverse cluster of cerebrovascular diseases primarily affecting small arteries, capillaries, arterioles and venules. The diagnosis of CSVD relies on the identification of small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, and microbleeds using neuroimaging. CSVD is observed in 25% of strokes worldwide and is the most common pathology of cognitive decline and dementia in the elderly. Still, due to the poor understanding of pathophysiology in CSVD, there is not an effective preventative or therapeutic approach for CSVD. The most widely accepted approach to CSVD treatment is to mitigate vascular risk factors and adopt a healthier lifestyle. Thus, a deeper understanding of pathogenesis may foster more specific therapies. Here, we review the underlying mechanisms of pathological characteristics in CSVD development, with a focus on endothelial dysfunction, blood-brain barrier impairment and white matter change. We also describe inflammation in CSVD, whose role in contributing to CSVD pathology is gaining interest. Finally, we update the current treatments and preventative measures of CSVD, as well as discuss potential targets and novel strategies for CSVD treatment.

Keywords: blood-brain barrier breakdown; cerebral small vessel disease; cognitive impairment; endothelial dysfunction; inflammation; white matter change.

FIGURE 1

The Neurovascular Unit (NVU). Vascular (endothelial cells and pericytes) and brain (astrocytes, oligodendrocytes, and neurons) cells interact and function as a unit, millions of which reside in the brain. Figure created using BioRender.com.

FIGURE 2

Pathological characteristics of cerebral small vessel disease (CSVD). Of them, decreased nitric oxide (NO) bioavailability is the most commonly used marker of dysfunction in endothelial cells (ECs). Reducing NO levels can lead to less vasodilation of neighboring smooth muscle cells, which in turn causes nitrosylation or nitrosation of tight junction (TJ) proteins, ultimately resulting in BBB disruption. Increased ET1 release by dysfunctional ECs can give rise to pathological vasoconstriction. The reduction of semaphorin 3G and sirt1 due to endothelial dysfunction can affect synaptic plasticity and BBB integrity respectively, and consequently, contribute to cognitive decline. Additionally, the factors secreted by dysfunctional ECs such as von Willebrand factor (vWF), heat shock protein 90α (HSP 90α), acid sphingomyelinase (ASM) and matrix metalloproteinases (MMPs) can induce vessel damage directly, as well as impair the integrity of the BBB and white matter. Compromising the BBB allows for entry of potential detrimental plasma components and immune cells into the brain parenchyma, further promoting BBB breakdown and white mater damage via neuroinflammation and direct neurotoxic effects. Figure created using BioRender.com.

FIGURE 3

Contributions of inflammation to cerebral small vessel disease (CSVD). Chronic hypertension-induced vascular remolding leads to hypoxia and ischemia of local brain parenchyma, thereby triggering activation of microglia. In addition, hypertension and aging can generate chronic, low-grade inflammation. The inflammatory molecules generated and immune cells recruited as a result contribute to BBB impairment and endothelial dysfunction. Figure created using BioRender.com.