MyD88-dependent signalling promotes the recruitment of fibrous cap smooth muscle cells in murine atherosclerosis.

BACKGROUND AND AIMS: Recruitment of fibrous cap smooth muscle cells (SMCs) is critical for stabilizing atherosclerotic plaques and preventing rupture. This study investigated the importance of the myeloid differentiation primary response protein 88 (Myd88) gene, encoding an adaptor protein essential for cytokine and pattern-recognition receptor signalling, for cap SMC recruitment during murine atherosclerosis.

METHODS: Myd88 knockdown was performed in cultured rat aortic SMCs, and the effects of inflammatory stimulation were assessed. SMC-specific Myd88 knockout mice were generated using Cre/lox recombination, and atherosclerosis was induced by proprotein convertase subtilisin/kexin type 9 (PCSK9) gene transfer followed by a high-fat diet for 12 or 20 weeks. Plaque size, composition, and fibrous cap SMC accumulation were analysed by immunofluorescence and in situ hybridization.

RESULTS: Myd88 knockdown preserved contractile gene expression under inflammatory stimulation, reduced SMC proliferation and migration, and enhanced contraction of SMC-infiltrated collagen gels. In hypercholesterolemic mice, SMC-specific Myd88 deficiency did not significantly alter plaque size in the aortic root but reduced the number of cap SMCs in advanced lesions at 20 weeks and in the most atherosclerosis-susceptible aortic sinus at 12 weeks. Other plaque features, including macrophages, necrotic core size, and collagen content, were not significantly affected. Notably, Myd88 deletion preserved the contractile phenotype of medial SMCs beneath plaques, suggesting that impaired phenotypic modulation contributed to reduced cap SMC recruitment.

CONCLUSIONS: MyD88-dependent signalling promotes medial SMC phenotypic modulation and the recruitment of cap SMCs, linking inflammatory signalling to protective fibrous cap formation in murine atherosclerosis.