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Role of pericytes in the development of cerebral cavernous malformations

Cerebral cavernous malformation (CCM) is caused by loss-of-function mutations in CCM1CCM2, or CCM3 genes of endothelial cells. It is characterized by pericyte deficiency. However, the role of pericytes in CCMs is not yet clarified. We found pericytes in Cdh5Cre ERT2 ;Ccm1 fl/fl (Ccm1 ECKO ) mice had a high expression of PDGFRβ. The inhibition of pericyte function by CP-673451 aggravated the CCM lesion development. RNA-sequencing analysis revealed the molecular traits of pericytes, such as highly expressed ECM-related genes, especially Fn1. Furthermore, KLF4 coupled with phosphorylated SMAD3 (pSMAD3) promoted the transcription of fibronectin in the pericytes of CCM lesions. RGDS peptide, an inhibitor of fibronectin, decreased the lesion area in the cerebella and retinas of Ccm1 ECKO mice. Also, human CCM lesions had abundant fibronectin deposition, and pSMAD3- and KLF4-positive pericytes. These findings indicate that pericytes are essential for CCM lesion development, and fibronectin intervention may provide a novel target for therapeutic intervention in such patients.

 

Comments:

Pericytes play a crucial role in the development of cerebral cavernous malformation (CCM) due to the high expression of PDGFRβ and fibronectin, and the inhibition of pericyte function by CP-673451 or fibronectin intervention using RGDS peptide may be a novel target for therapeutic intervention in CCM patients.

Related Products

Cat.No. Product Name Information
S1536 CP-673451 CP-673451 is a selective inhibitor of PDGFRα/β with IC50 of 10 nM/1 nM in cell-free assays, exhibits >450-fold selectivity over other angiogenic receptors, has antiangiogenic and antitumor activity.

Related Targets

PDGFR