Abstract WP389: Unraveling Cerebral Cavernous Malformation Pathogenesis: Insights from a Radiation-Induced Endothelial Dysmorphism Model

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Introduction: Mouse models have been a valuable tool for studying the molecular mechanisms driving cerebral cavernous malformation (CCM) pathogenesis. However, genetically modified mouse models do not fully recapitulate human CCM disease, and endothelial dysfunction is implicated in multiple disease processes of the brain. Herein, we provide a radiation-induced platform of endothelial dysmorphism and physiologic dysfunction similar to that observed in CCM disease. By analyzing gene expression and pathway alterations in endothelial cells, this model enhances our understanding of the fundamental biological processes at play that are common and different between CCM and endothelial leak. Methods: Ten-week-old female C57BL/6 mice underwent irradiation with 40 Gy (@50% isodose) to a 5mm target within the left cerebral hemisphere. Brain parenchymal changes were assessed using contrast-enhanced CT imaging and histology. Endothelial cell RNA extraction and transcriptomic analysis were performed on formalin-fixed, paraffin-embedded coronal tissue sections from radiated and control hemispheres using the a digital spatial profiler system. Ingenuity Pathway Analysis (IPA) was employed to identify affected molecular pathways. Results: CT imaging revealed increased blood-brain barrier permeability within the irradiated area. Histologic analysis identified telangiectasias and microhemorrhages, consistent with dysmorphic endothelium and capillary malformations. Gene expression profiles between radiated vs. non-radiated endothelium demonstrated a clear distinction by principal component analysis. Differentially expressed genes were primarily associated with extracellular matrix organization, regulation of the actin cytoskeleton, and pro-inflammatory cytokine response pathways. Upstream analysis predicted TGFB1, TNF, lipopolysaccharide, dexamethasone, and angiotensinogen as potential regulators underlying the observed changes. Conclusion: This study elucidates a signature of dysmorphic endothelium in a non-genetically modified mouse model, revealing potential key molecular pathways and regulators that lead to endothelial leak. This model can guide mechanistic-based experimental studies and provide a platform for targeted interventions directed at critical components of CCM pathophysiology and the blood-brain barrier.

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