C1q/TNF‐related protein 4 mediates proliferation and migration of vascular smooth muscle cells during vascular remodelling

• Published in: Clinical and translational medicine Vol. 13; no. 5; pp. e1261 - n/a
• Main Authors: Liu, Jingying, Long, Xingbo, Li, Hexin, Yan, Qiuxia, Wang, Lu, Qin, Ziyu, Zhang, Hong
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.05.2023; John Wiley and Sons Inc; Wiley
• Subjects: Amino acids; Angioplasty; Animals; Apoptosis; Atherosclerosis; Biomarkers; C1QTNF4; Cardiovascular Diseases; Cell Proliferation; Clinical medicine; Complement C1q; Constriction, Pathologic; Disease; Extracellular matrix; Growth factors; Humans; Hyperplasia; Inflammation; Kinases; Laboratory animals; Mice; Muscle, Smooth, Vascular; neointima formation; Phosphatidylinositol 3-Kinases; proliferation and migration; Proteins; Proto-Oncogene Proteins c-akt; Rats; Smooth muscle; Software; Vascular Remodeling; vascular remodelling; vascular smooth muscle cell; C1QTNF4; neointima formation; vascular remodelling; vascular smooth muscle cell; proliferation and migration
• ISSN: 2001-1326; 2001-1326
• DOI: 10.1002/ctm2.1261

Background Vascular remodelling is an essential pathophysiological state in many circulatory diseases. Abnormal vascular smooth muscle cell (VSMC) behaviour leads to neointimal formation and may eventually results in major adverse cardiovascular events. The C1q/TNF‐related protein (C1QTNF) family is closely associated with cardiovascular disease. Notably, C1QTNF4 has unique two C1q domains. However, the role of C1QTNF4 in vascular diseases remains unclear. Methods C1QTNF4 expression was detected in human serum and artery tissues using ELISA and multiplex immunofluorescence (mIF) staining. Scratch assay, transwell assay and confocal microscopy were used to investigate C1QTNF4 effects on VSMC migration. EdU incorporation, MTT assay and cell counting experiment revealed C1QTNF4 effects on VSMC proliferation. C1QTNF4‐transgenic, C1QTNF4−/− and AAV9‐mediated VSMC‐specific C1QTNF4 restoration C1QTNF4−/‐ mouse and rat disease models were generated. RNA‐seq, quantitative real‐time PCR, western blot, mIF, proliferation and migration assays were used to investigate the phenotypic characteristics and underlying mechanisms. Results Serum C1QTNF4 levels were decreased in patients with arterial stenosis. C1QTNF4 shows colocalisation with VSMC in human renal arteries. In vitro, C1QTNF4 inhibits VSMC proliferation and migration and alters VSMC phenotype. In vivo, an adenovirus‐infected rat balloon injury model, C1QTNF4‐transgenic and C1QTNF4−/− mouse wire‐injury models with or without VSMC‐specific C1QTNF4 restoration were established to mimic the VSMC repair and remodelling. The results show that C1QTNF4 decreases intimal hyperplasia. Especially, we displayed the rescue effect of C1QTNF4 in vascular remodelling using AAV vectors. Next, transcriptome analysis of artery tissue identified the potential mechanism. In vitro and in vivo experiments confirm that C1QTNF4 ameliorates neointimal formation and maintains vascular morphology by downregulating the FAK/PI3K/AKT pathway. Conclusions Our study demonstrated that C1QTNF4 is a novel inhibitor of VSMC proliferation and migration that acts by downregulating the FAK/PI3K/AKT pathway, thus protecting blood vessels from abnormal neointima formation. These results provide new insights into promising potent treatments for vascular stenosis diseases. C1QTNF4 levels reduce in carotid artery stenosis patients. C1QTNF4 is an important regulator of vascular smooth muscle cell proliferation, migration and alters vascular smooth muscle cell phenotype. C1QTNF4 treatment can effectively ameliorate vascular remodelling. C1QTNF4 negatively regulates the FAK/PI3K/AKT pathway, thus protecting blood vessels from abnormal neointima formation and maintains vascular morphology.