Neurovascular Mechanisms in Schizophrenia

The pathophysiology of schizophrenia increasingly implicates neurovascular dysfunction, notably disturbances of the blood–brain barrier (BBB) and the broader neurovascular unit. Endothelial cells, pericytes and astrocytes normally coordinate to regulate cerebral perfusion, nutrient transport and immune surveillance. In schizophrenia, tight-junction breakdown and elevated endothelial permeability permit neurotoxic molecules and peripheral immune mediators to access the brain parenchyma, fuelling neuroinflammation. Altered angiogenesis and dysregulated vascular endothelial growth factor signalling contribute to abnormal microvasculature density, while impaired cerebral blood flow associates with cognitive deficits. Glial cells respond to barrier disruption by releasing S100B and pro-inflammatory cytokines, further modulating neurotransmitter systems and oxidative stress pathways. These neurovascular alterations intersect with dopaminergic and glutamatergic dysfunction, exacerbating synaptic disconnection and clinical symptoms. Biomarkers of barrier integrity in blood and cerebrospinal fluid could inform patient stratification, and targeting endothelial or astrocytic mechanisms offers novel therapeutic avenues. Integrating vascular biology into models of schizophrenia may reconcile genetic and environmental risk factors through a shared vascular-immune framework, underscoring the global significance of neurovascular research for precision psychiatry.

Research from Nature Portfolio

Recent studies have demonstrated that plasma concentrations of the glial protein S100B are elevated in individuals with schizophrenia and correlate with systemic inflammatory markers. Detailed analyses reveal that the balance of pro- and anti-inflammatory cytokines independently predicts S100B levels, implicating an interplay between immune regulation and glial dysfunction. These findings support the concept that peripheral immune responses contribute to neurovascular compromise by modulating astrocytic activity and barrier integrity, highlighting S100B as a candidate biomarker for barrier disruption and disease progression.

Neurovascular Mechanisms in Schizophrenia publication trend

The graph below shows the total number of articles in neurovascular mechanisms in schizophrenia across all publications each year (not limited to Nature Index journals).

Technical terms

Blood–brain barrier (BBB): A specialised endothelial barrier that regulates the passage of substances between blood and brain tissue.

Neurovascular unit (NVU): The functional ensemble of endothelial cells, astrocytes, pericytes and neurons that maintains cerebral homeostasis.

Endothelial permeability: The propensity of the vascular endothelium to allow molecules and cells to pass through intercellular junctions.

Angiogenesis: The process of new blood vessel formation from existing vasculature, critical for tissue perfusion and repair.

S100B protein: A calcium-binding marker of glial activation and barrier integrity, often measured to assess neurovascular damage.

References

1. Association of symptom severity and cerebrospinal fluid alterations in recent onset psychosis in schizophrenia-spectrum disorders – An individual patient data meta-analysis. Brain Behavior and Immunity (2024).
2. Schizophrenia endothelial cells exhibit higher permeability and altered angiogenesis patterns in patient-derived organoids. Translational Psychiatry (2024).
3. The Cellular Dysfunction of the Brain–Blood Barrier from Endothelial Cells to Astrocytes: The Pathway towards Neurotransmitter Impairment in Schizophrenia. International Journal of Molecular Sciences (2024).
4. Neurovascular Unit Dysfunction and Blood–Brain Barrier Hyperpermeability Contribute to Schizophrenia Neurobiology: A Theoretical Integration of Clinical and Experimental Evidence. Frontiers in Psychiatry (2017).
5. The Inflamed Brain in Schizophrenia: The Convergence of Genetic and Environmental Risk Factors That Lead to Uncontrolled Neuroinflammation. Frontiers in Cellular Neuroscience (2020).
6. PKA activation and endothelial claudin-5 breakdown in the schizophrenic prefrontal cortex. Oncotarget (2017).
7. Higher Plasma S100B Concentrations in Schizophrenia Patients and Dependently Associated with Inflammatory Markers. Scientific Reports (2016).
8. Vascular Endothelial Growth Factor and Brain‐Derived Neurotrophic Factor in Quetiapine Treated First‐Episode Psychosis. Schizophrenia Research and Treatment (2014).