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bioRxiv · 10.1101/2025.07.01.662493

MyD88-dependent signaling promotes smooth muscle cell phenotypic modulation and fibrous cap formation in murine atherosclerosis

Gunnersen, S.·Albarran-Juarez, J.·Jensen, L. F.·Shim, J. T.·Sorensen, C. B.·Bentzon, J. F.
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Abstract

Background and aimsRecruitment of fibrous cap smooth muscle cells (SMCs) is critical for stabilizing atherosclerotic plaques and preventing rupture. This study investigated the SMC-specific role of the myeloid differentiation primary response protein 88 (Myd88) gene, encoding an adaptor protein essential for signaling downstream of several cytokine and pattern-recognition receptors, in this process. MethodsThe effects of MyD88 knockdown were assessed in cultured rat aortic SMCs. SMC-specific knockout of Myd88 was induced in mice using the Cre/lox method, followed by induction of atherosclerosis by proprotein convertase subtilisin/kexin type 9 gene transfer and a high-fat diet for 12 or 20 weeks. Effects on plaque and fibrous cap formation were studied by immunofluorescence and in situ hybridization. ResultsMyd88 knockdown reduced proliferation and migration of cultured SMCs and preserved contractile gene expression under inflammatory stimulation. SMC-specific Myd88 deficiency in hyperlipidemic mice 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 deficiency preserved the contractile phenotype of medial SMCs beneath plaques, suggesting that impaired phenotypic modulation contributed to reduced cap SMC recruitment. ConclusionsMyD88-dependent signaling promotes medial SMC phenotypic modulation and the recruitment of fibrous cap SMCs during atherogenesis. These findings highlight MyD88 as a mediator linking inflammatory signaling to protective fibrous cap formation. HighlightsO_LIKnockdown of MyD88 preserves the contractile phenotype of cultured smooth muscle cells subjected to inflammatory cytokines. C_LIO_LITargeting MyD88 in murine atherosclerosis inhibits fibrous cap formation. C_LIO_LITargeting MyD88 in murine atherosclerosis preserves the contractile phenotype of medial smooth muscle cells beneath the plaque. C_LI

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Gunnersen, S., Albarran-Juarez, J., Jensen, L. F., Shim, J. T., Sorensen, C. B., Bentzon, J. F.. 2025-07-04. MyD88-dependent signaling promotes smooth muscle cell phenotypic modulation and fibrous cap formation in murine atherosclerosis. https://doi.org/10.1101/2025.07.01.662493

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