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Updated: Sep 6, 2025
On-Chip Endothelial Inflammatory Phenotyping
Published on: July 21, 2012
Transcriptome Analysis Reveals Altered Expression of Genes Involved in Hypoxia, Inflammation and Immune Regulation in
Carmela Fusco1, Grazia Nardella1, Lucio Di Filippo2
1Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, 71013 Foggia, Italy.
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.
Insights
Researchers identified key molecular pathways involved in cerebral cavernous malformations (CCM). Silencing PDCD10 in mouse endothelial cells revealed significant gene expression changes related to inflammation and pathogen recognition, offering new insights into CCM pathogenesis.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Cerebral cavernous malformations (CCM) are vascular defects in the central nervous system, leading to symptoms like headaches, epilepsy, and stroke.
- Current CCM treatments are symptomatic, and preventative strategies are limited.
- Familial CCM can be caused by pathogenic variants in PDCD10, representing a severe genetic subtype.
Purpose of the Study:
- To elucidate the molecular pathogenesis of CCM, particularly the role of PDCD10.
- To identify differentially expressed genes in endothelial cells associated with PDCD10 deficiency.
Main Methods:
- RNA-sequencing (RNA-Seq) was performed on Pdcd10-silenced and wild-type mouse endothelial cells.
- Quantitative PCR (Q-PCR) was used for validation analysis.
- Functional clustering of differentially expressed genes was analyzed.
Main Results:
- Ninety-four differentially expressed genes were identified with a false discovery rate (FDR)-corrected p-value < 0.05.
- Gene ontology analysis revealed clusters related to cell proliferation, oxidative stress, vascular processes, and immune response.
- A significant cluster involved signaling pathways related to inflammation and pathogen recognition, including HIF1α and Nos2.
Conclusions:
- This study confirms previous transcriptomic findings in endothelial cells, crucial for CCM development.
- The findings expand the molecular understanding of PDCD10-related familial CCM to include alterations in inflammation and pathogen recognition pathways.
- These insights may pave the way for novel therapeutic targets for CCM.
