Role of pericytes in the development of cerebral cavernous malformations

Cerebral cavernous malformation (CCM) is caused by loss-of-function mutations in CCM1, CCM2, or CCM3 genes of endothelial cells. It is characterized by pericyte deficiency. However, the role of pericytes in CCMs remains poorly understood. Our study showed that pericytes in Cdh5CreERT2; Ccm1fl/fl (Ccm1ECKO) mice were high expression of PDGFRß. The inhibition of pericyte function by CP-673451 aggravated the CCM lesion development. RNA-seq analysis revealed the molecular traits of pericytes, such as highly expressed ECM-related genes, especially Fn1. Furthermore, KLF4 coupled with phosphorylated SMAD3 promoted the transcription of fibronectin in pericytes of CCM lesions. RGDS peptide, an inhibitor of fibronectin, decreased the lesion area in the cerebella and retinas of Ccm1ECKO mice. Also, human CCM lesions had abundant fibronectin deposition, and pSMAD3- and KLF4-positive pericytes. The current data demonstrated that pericytes are essential for CCM lesion development, and fibronectin intervention may provide a novel target for therapeutic intervention in such patients. Overall design: Comparative gene expression profiling analysis of RNA-seq data for pericytes purified from Ccm1fl/fl mice and Cdh5Cre/+ERT2;Ccm1fl/fl mice treated by 4-hydroxy-tamoxifen. Three independent biological replicates were used for the analysis.