Abstract

Introduction: Atherogenesis involves a complex interaction between immune cells and lipids, processes greatly influenced by the vascular smooth muscle cells (VSMCs) phenotype. Cellular communication network factor 2 (CCN2) is a matricellular protein with an established role in maintaining tissue and organ homeostasis. Various studies have demonstrated the importance of CCN2 in regulating cardiovascular diseases, however its role in atherosclerosis remains to be investigated. Hypothesis: SMC-restricted CCN2 deficiency exacerbates atherosclerosis development in murine models through the modulation of SMC phenotype switching. Aim: Determine the role of VSMC-derived CCN2 in regulating atherosclerosis progression. Methods: In this study, CCN2 was deleted in VSMCs using Cre-lox technology. To induce atherosclerosis, mice were rendered LDLR deficient via AAV8-PCSK9 injection, followed by administration of a high-fat diet for 20 weeks. Aortic atherosclerotic lesion development was then assessed along with single-cell RNA sequencing to map the molecular effects of CCN2 deficiency on the VSMCs phenotype. Gain and loss of function studies in VSMCs were performed to assess the impact of CCN2 alteration on VSMC phenotype switching. Results: SMC-specific CCN2 knockout (SMC-CCN2-KO) mice demonstrated exquisite susceptibility to atherosclerosis formation as evidenced by a significant increase of aortic lipid-rich plaques in aortic roots, arch, thoracic and abdominal aorta. Concomitant with this, a profound vascular inflammation was seen in SMC-CCN2-KO mice. Importantly, these phenotypic changes were associated with a dramatic shift in VSMC phenotype towards a proliferating, lipid-accumulating and macrophage-like cell phenotype. Mechanistic studies point to the requisite role of the KLF4 pathway in VSMC transdifferentiation in SMC-CCN2-KO mice, findings corroborated by cell culture experiments in which KLF4-dependent phenotypic changes were observed in CCN2-null human primary aortic VSMCs. Conclusions: Our findings show that CCN2 deficiency in VSMCs promotes atherosclerosis development through affecting the VSMC phenotypic transition into macrophage-like cells by activation of the KLF4 signaling pathway.

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