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
Affiliations
Zifeng Dai
Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, Heilongjiang Province 150001, PRC China
Jingwei Li
Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, Heilongjiang Province 150001, PRC China
Ying Li
Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, Heilongjiang Province 150001, PRC China
Rui Wang
Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, TianJin 300070, PRC China
Huili Yan
Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, TianJin 300070, PRC China
Ziyu Xiong
Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, Heilongjiang Province 150001, PRC China
Shiting Wu
Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, TianJin 300070, PRC China
Xi Yang
Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, TianJin 300070, PRC China
Dongbo Lu
Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, TianJin 300070, PRC China
Dongdong Zhang
Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, Heilongjiang Province 150001, PRC China
Guofu Li
Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, Heilongjiang Province 150001, PRC China
Yuwen Wang
Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, Heilongjiang Province 150001, PRC China
Chunyang Men
Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, Heilongjiang Province 150001, PRC China
Wenzhong Du
Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, Heilongjiang Province 150001, PRC China
Xiangjian Zheng
Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, TianJin 300070, PRC China
Changbin Shi
Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, Heilongjiang Province 150001, PRC China; Corresponding author
Summary: 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 Cdh5CreERT2;Ccm1fl/fl (Ccm1ECKO) 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 Ccm1ECKO 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.
