Therapeutic Implication of Anti-CTGF in Neointimal Hyperplasia via Regulating Mitochondrial Dysfunction and VSMC...

Connective tissue growth factor (CTGF), also known as CCN2, is a matricellular protein of the CCN family (CCN1-6) that regulates the proliferation of vascular smooth muscle cells (VSMCs), thereby contributing to the pathogenesis of atherosclerosis and hypertension. However, the intercellular signaling pathway that CTGF takes for vascular remodeling, such as VSMC phenotype transition, has not been fully elucidated. This study employed a combination of in vivo and in vitro tests to examine VSMC phenotype and reveal the role of CTGF in vascular remodeling induced by angiotensin II (Ang II). The in vitro experiments showed that Ang II upregulated CTGF expression in rat VSMCs in a concentration- and time-dependent manner. Genetic depletion of CTGF with siRNA against rat Ccn2 prevented Ang II-induced autophagic flux impairment. In addition, Ang II-induced phenotypic switch was inhibited by 3-MA, an inhibitor of autophagy, suggesting CTGF is involved in Ang II-induced phenotypic switch via regulating autophagic flux impairment. In addition, this CTGF-dependent autophagy regulation was involved in Ang II-induced mitochondrial dysfunction in VSMCs. Moreover, anti-CTGF antibody treatment inhibited neointimal hyperplasia in a mouse model of carotid artery ligation-induced neointima formation suggesting a novel perspective role of CTGF in the phenotype switching of VSMCs and the neointimal proliferation process. These results offer insights into the effect of anti-CTGF on preventing autophagic flux impairment and VSMC phenotype switching caused by mitochondrial dysfunction in vascular diseases associated with aberrant VSMC proliferation.