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

• DOI: 10.1161/str.56.suppl_1.wp389
• Publication Date: 2025-01-30T10:12:34Z
• Authors: Roberto Alcazar; Abhinav Srinath; David Tieri; Diana Vera Cruz; Sammy Allaw; Dominic Montas; Fidel Haro; Erik Pearson; Peter Pytel; Issam Awad; Sean Polster
• Keywords: Pathogenesis; Facial dysmorphism

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