Abstract
Cerebral small vessel disease (SVD) is highly prevalent and a common cause of ischemic and hemorrhagic stroke and dementia, yet the pathophysiology is poorly understood. Its clinical expression is highly varied, and prognostic implications are frequently overlooked in clinics; thus, treatment is currently confined to vascular risk factor management. Traditionally, SVD is considered the small vessel equivalent of large artery stroke (occlusion, rupture), but data emerging from human neuroimaging and genetic studies refute this, instead showing microvessel endothelial dysfunction impacting on cell-cell interactions and leading to brain damage. These dysfunctions reflect defects that appear to be inherited and secondary to environmental exposures, including vascular risk factors. Interrogation in preclinical models shows consistent and converging molecular and cellular interactions across the endothelial-glial-neural unit that increasingly explain the human macroscopic observations and identify common patterns of pathology despite different triggers. Importantly, these insights may offer new targets for therapeutic intervention focused on restoring endothelial-glial physiology.
Highlights
This review focuses on pathophysiological mechanisms identified in humans that contribute to brain damage seen in cerebral small vessel disease (SVD), using evidence from humans with covert, stroke-related, or cognitive impairments due to SVD and corresponding evidence from experimental models
We found differential gene expression in spontaneously hypertensive rat stroke prone (SHRSP) at 5 weeks of age for genes related to Endothelial cells (ECs) tight junctions, nitric oxide (NO) bioavailability and albumin, myelination, matrix proteins and vascular reactivity, and glial and microglial activity, compared with WKY controls [125], which we confirmed at the protein level at all three time points [126]
The action of this single nucleotide polymorphisms (SNPs) on ATP11B expression remains unknown. These findings indicate that an intrinsic EC dysfunction, independent of hypertension, due to a deletion in Atp11b and loss of ATP11B protein, causes several key abnormalities highly consistent with human SVD: impaired EC tight junctions [susceptible to blood–brain barrier (BBB) leakage [70]], reduction in endothelial NO synthase and NO [impaired vasoreactivity [72]], and blocked maturation of oligodendrocyte precursor cell (OPC)
Summary
This review focuses on pathophysiological mechanisms identified in humans that contribute to brain damage seen in cerebral small vessel disease (SVD), using evidence from humans with covert, stroke-related, or cognitive impairments due to SVD and corresponding evidence from experimental models. Knockdown of the Atp11b/ATP11B gene in cultured wild-type rodent or human ECs caused a similar dysfunctional phenotype to that of the SHRSP, including EC proliferation with fewer tight junctions, reduced NO, increased secretion of HSP90α, and treatment of OPCs with medium conditioned by these cells led to increased OPC proliferation and impaired maturation These changes were partially rescued in intact SHRSPs by treatment between 5 and 12 weeks of age with three drugs known to have endothelial-stabilizing effects via different pathways (perindopril, simvastatin, and cilostazol). The action of this SNP on ATP11B expression remains unknown These findings indicate that an intrinsic EC dysfunction, independent of hypertension, due to a deletion in Atp11b and loss of ATP11B protein, causes several key abnormalities highly consistent with human SVD: impaired EC tight junctions [susceptible to BBB leakage [70]], reduction in endothelial NO synthase and NO [impaired vasoreactivity [72]], and blocked maturation of OPCs. OPC: oligodendrocyte precursor cell; cell that matures into an oligodendrocyte that forms myelin. Cilostazol has evidence of benefit in secondary stroke prevention in lacunar stroke [144] and in trials to prevent SVD worsening, providing hope for effective future therapies
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