Abstract TMP15: Transcriptomic Signatures Of Individual Cell Types In Cavernous Angioma

Abstract

Introduction: Cavernous Angiomas (CAs) are vascular malformations characterized by clusters of blood-filled capillary spaces lined by “leaky” endothelium. While mutations in endothelial cells have long been recognized as necessary for lesion genesis, there is evidence of inflammation, response to hypoxia, and non-endothelial autonomous cell effects driving pathogenesis. Disrupted gene expression in the CA neurovascular unit (NVU) has been described but the contribution of each cell type has not been previously investigated. Methods: Six CA and four control brain samples were collected and frozen during surgical resection. The endothelial cells, pericytes, and neuroglia (astrocytes and neurons) were sorted, and the RNA was extracted and sequenced. The differentially expressed genes (DEGs) were identified ( p <0.05, FDR corrected) for each cell type. Enrichment pathway analyses were performed through Ingenuity Pathway Analyses (IPA, Qiagen; p <0.05, FDR corrected), Gene Ontology (GO; p <0.1, FDR corrected) and Kyoto Encyclopedia of Genes and Genomes (KEGG; p <0.1, FDR corrected). Results: In endothelial cells, 362 DEGs were identified contributing to 54 enriched IPA pathways. In addition, 484 DEGs were found in pericytes and 50 IPA pathways were identified. The common functions between these two cell types were related to angiogenesis, extracellular matrix organization, cell adhesion, and platelet activation, while the function related to response to hypoxia was only shown in pericytes. Finally, 242 DEGs and 52 IPA pathways were identified in neuroglia cells. The associated pathway functions were related to inflammatory response and cell adhesion. The IPA results were further confirmed by the GO term and KEGG pathway analyses. Conclusion: We confirm that disrupted genes related to angiogenesis, blood-brain barrier integrity, cell adhesion and platelet activation in the CA lesion involve endothelial cells and pericytes primarily. Pericytes are particularly associated with disrupted genes related to response to hypoxia, while neuroglia is associated with greater gene disruptions related to inflammation. These results motivate novel mechanistic hypotheses regarding non-endothelial cell contributions to lesion pathobiology.