Vascular endothelial cadherin remodeling is associated with endothelial barrier dysfunction in chronic subdural hematoma
Abstract Background: Chronic subdural hematoma (cSDH) remains a significant and increasingly prevalent cause of morbidity in older adults. Disease progression is sustained by de novo formed highly vascularized pseudomembranes and a persistent cycle of fluid accumulation and hematoma expansion. Although inflammatory and angiogenic pathways have been implicated in cSDH pathogenesis, the endothelial…
Background: Chronic subdural hematoma (cSDH) is a common and growing cause of long-term health issues in older individuals. It is caused by de novo formed vascularized pseudomembranes and a continuous cycle of fluid buildup and hematoma growth. While inflammatory and angiogenic pathways have been tied to cSDH development, the endothelial factors responsible for persistent vascular permeability are not well understood.
This study aimed to investigate the vascular environment in cSDH patients and determine the impact of vascular endothelial cadherin (VECAD) remodeling on cSDH endothelial dysfunction.
Methods: Human cSDH samples and fluid were analyzed using multiplex profiling, histology, immunofluorescence, immunoprecipitation, western blotting, and exploratory bulk RNA sequencing. Additionally, a human brain endothelial cell (HBEC) line was exposed to patient-derived cSDH fluid to evaluate VECAD remodeling, endothelial barrier permeability, and cell proliferation.
Results: Analysis of patient-derived cSDH fluid revealed mediators linked to EC activation, extracellular matrix remodeling, inflammation, and angiogenesis. Discontinuous VECAD was found in patient pseudomembranes, which correlated with erythrocyte extravasation. Two types of specimens, hyperdense (high-risk) and hypodense (low-risk), demonstrated varying degrees of VECAD disruption. The hyperdense specimens showed more extensive disruption compared to the hypodense sample, despite similar vessel counts.
Bulk RNA sequencing revealed an angiogenic environment and cadherin regulation enrichment. A soluble form of VECAD (sVECAD) was detected in cSDH fluid. When HBECs were exposed to patient-derived cSDH fluid, EC proliferation, cytoplasmic VECAD accumulation, and EC barrier permeability increased. Dexamethasone or minocycline treatment, administered concurrently with the fluid exposure, helped reduce VECAD cleavage.
Conclusions: Disruption of VECAD is a significant feature of cSDH and is associated with endothelial barrier dysfunction. These findings suggest that soluble VECAD could be a potential biomarker, and junction-preserving pathways may serve as promising therapeutic targets for cSDH management.
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