Transcriptome Analysis Reveals Altered Expression of Genes Involved in Hypoxia, Inflammation and Immune Regulation in Pdcd10-Depleted Mouse Endothelial Cells

Abstract

Cerebral cavernous malformations (CCM) are capillary malformations affecting the central nervous system and commonly present with headaches, epilepsy and stroke. Treatment of CCM is symptomatic, and its prevention is limited. CCM are often sporadic but sometimes may be multifocal and/or affect multiple family members. Heterozygous pathogenic variants in PDCD10 cause the rarest and apparently most severe genetic variant of familial CCM. We carried out an RNA-Seq and a Q-PCR validation analysis in Pdcd10-silenced and wild-type mouse endothelial cells in order to better elucidate CCM molecular pathogenesis. Ninety-four differentially expressed genes presented an FDR-corrected p-value < 0.05. A functionally clustered dendrogram showed that differentially expressed genes cluster in cell proliferation, oxidative stress, vascular processes and immune response gene-ontology functions. Among differentially expressed genes, the major cluster fell in signaling related to inflammation and pathogen recognition, including HIF1α and Nos2 signaling and immune regulation. Validation analysis performed on wild-type, Pdcd10-null and Pdcd10-null reconstituted cell lines was consistent with RNA-Seq data. This work confirmed previous mouse transcriptomic data in endothelial cells, which are recognized as a critical tissue for CCM formation and expands the potential molecular signatures of PDCD10-related familial CCM to alterations in inflammation and pathogen recognition pathways.

The First Potentially Causal Genetic Variant Documented in a Polish Woman with Multiple Cavernous Malformations of the Brain

“…In a more overall, international perspective, genetic testing is becoming one of the main inclusion criteria in clinical trials aimed at finding the optimal therapeutic approaches for FCCM [ 22 , 27 , 28 , 29 ]. Further studies, particularly clinical trials [ 27 , 28 , 29 ], along with more basic experimental investigations should clarify the molecular and cellular bases of CCM, identify new therapeutic targets [ 24 , 30 ], and thus help to optimize treatment strategies in affected subjects.…”

Inflammatory Mechanisms in a Neurovascular Disease: Cerebral Cavernous Malformation

“…These results suggest that a mutation in the CCM gene affects innate immunity pathways. Fusco et al (2022) published transcriptome analyses revealing altered expression of genes involved in hypoxia, inflammation, and immune regulation in Ccm3 ( Pdcd10 )-depleted mouse endothelial cells [ 56 ].…”