Transcriptome clarifies mechanisms of lesion genesis versus progression in models of Ccm3 cerebral cavernous malformations

• DOI: 10.1186/s40478-019-0789-0
• Publication Date: 2019-08-19T08:02:43Z
• Authors: Janne Koskimäki; Dongdong Zhang; Yan Li; Laleh Saadat; Thomas Moore; Rhonda Lightle; Sean P. Polster; Julián Carrión-Pe...; Seán B. Lyne; Hussein A. Zeined...; Changbin Shi; Robert Shenkar; Sharbel Romanos; Kenneth Avner; Abhinav Srinath; Le Shen; Matthew R. Detter; Daniel Snellings; Ying Cao; Miguel A. Lopez-R...; Gregory Fonseca; Alan T. Tang; Pieter Faber; Jorge Andrade; Mark Ginsberg; Mark L. Kahn; Douglas A. Marchuk; Romuald Girard; Issam A. Awad
• Keywords: Cavernous malformations

Cerebral cavernous malformations (CCMs) are dilated capillaries causing epilepsy and stroke. Inheritance of a heterozygous mutation in CCM3/PDCD10 is responsible for the most aggressive familial form disease. Here we studied differences commonalities between transcriptomes microdissected lesional neurovascular units (NVUs) from acute chronic vivo Ccm3/Pdcd10ECKO mice, cultured brain microvascular endothelial cells (BMECs) Ccm3/Pdcd10ECKO.We identified 2409 differentially expressed genes (DEGs) 2962 NVUs compared to capillaries, as well 121 vitro BMECs with without Ccm3/Pdcd10 loss (fold change ≥ |2.0|; p < 0.05, false discovery rate corrected). A functional clustered dendrogram generated using Euclidean distance showed that DEGs only were cellular proliferation gene ontology functions. The inflammation immune response, permeability, adhesion In addition, 1225 but not BMECs, these within neuronal glial One miRNA mmu-miR-3472a was (FC = - 5.98; 0.07, FDR corrected) serum Ccm3/Pdcd10+/- when wild type this functionally related putative target Cand2 (cullin associated neddylation dissociated 2), DEG BMECs. Our results suggest model characterized by cell proliferation, while inflammatory, permeability processes. highlight importance extra-endothelial structures CCM disease, potential role circulating miRNAs biomarkers interacting DEGs. extensive library each will serve validation tool mechanistic, biomarker, therapeutic targets.