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Cerebral Vascular Dysfunctions Detected in Human Small Vessel Disease and Implications for Preclinical Studies
Joanna M Wardlaw1, Helene Benveniste2, Anna Williams3
1Division of Neuroimaging Sciences, Centre for Clinical Brain Sciences; UK Dementia Research Institute; and Edinburgh Imaging, University of Edinburgh, Edinburgh, United Kingdom;
Insights
Cerebral small vessel disease (SVD) causes stroke and dementia, but its origins are unclear. New research shows microvessel endothelial dysfunction, not just vascular risk factors, drives SVD, offering potential new therapeutic targets.
Area of Science:
- Neuroscience
- Vascular Biology
- Pathophysiology
Background:
- Cerebral small vessel disease (SVD) is a prevalent condition causing stroke and dementia.
- Current understanding of SVD pathophysiology is limited, with treatment focused on vascular risk factors.
- Traditional views of SVD as a small vessel counterpart to large artery disease are being challenged.
Purpose of the Study:
- To explore the underlying pathophysiology of cerebral small vessel disease.
- To investigate the role of microvessel endothelial dysfunction in SVD.
- To identify potential new therapeutic targets for SVD.
Main Methods:
- Analysis of human neuroimaging and genetic studies.
- Investigation of preclinical models of SVD.
- Examination of molecular and cellular interactions within the endothelial-glial-neural unit.
Main Results:
- Human studies and preclinical models suggest SVD stems from microvessel endothelial dysfunction.
- Endothelial dysfunction impacts cell-cell interactions, leading to brain damage.
- Converging molecular and cellular evidence explains macroscopic SVD observations.
Conclusions:
- SVD pathophysiology involves inherited defects and environmental exposures affecting endothelial-glial-neural interactions.
- Microvessel endothelial dysfunction is a key driver of SVD, distinct from large artery disease.
- Understanding these mechanisms opens avenues for novel therapeutic interventions targeting endothelial-glial physiology.
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.
