Role of pericytes in the development of cerebral cavernous malformations

Zifeng Dai; Jingwei Li; Ying Li; Rui Wang; Huili Yan; Ziyu Xiong; Shiting Wu; Xi Yang; Dongbo Lu; Dongdong Zhang; Guofu Li; Yuwen Wang; Chunyang Men; Wenzhong Du; Xiangjian Zheng; Changbin Shi

doi:10.1016/j.isci.2022.105642

Role of pericytes in the development of cerebral cavernous malformations

iScience. 2022 Nov 19;25(12):105642. doi: 10.1016/j.isci.2022.105642. eCollection 2022 Dec 22.

Authors

Zifeng Dai¹, Jingwei Li¹, Ying Li¹, Rui Wang², Huili Yan², Ziyu Xiong¹, Shiting Wu², Xi Yang², Dongbo Lu², Dongdong Zhang¹, Guofu Li¹, Yuwen Wang¹, Chunyang Men¹, Wenzhong Du¹, Xiangjian Zheng², Changbin Shi¹

Affiliations

¹ Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, Heilongjiang Province 150001, PRC China.
² Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, TianJin 300070, PRC China.

Abstract

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 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.

Keywords: Clinical neuroscience; Neuroanatomy; Neuroscience.