Biology subjects

Gunnersen, S.

Publications and source records attributed to Gunnersen, S..

2 recordsLinked to original sources

bioRxiv2025

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

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

pathology↗

bioRxiv2023

Conditional deletion of Ccl2 in smooth muscle cells does not reduce early atherosclerosis in mice

Background and aimsC-C motif chemokine ligand 2 (CCL2) is a pro-inflammatory chemokine important for monocyte recruitment to the arterial wall and atherosclerotic plaques. Global knockout of Ccl2 reduces plaque formation and macrophage content in mice, but the importance of different plaque cell types in mediating this effect has not been resolved. Smooth muscle cells (SMCs) can adopt a potentially pro-inflammatory function with expression of CCL2. The present study aimed to test the hypothesis that SMC-secreted CCL2 is involved in early atherogenesis in mice. MethodsSMC-restricted Cre recombinase was activated at 6 weeks of age in mice with homozygous floxed or wildtype Ccl2 alleles. Separate experiments in mice lacking the Cre recombinase transgene were conducted to control for genetic background effects. Hypercholesterolemia and atherosclerosis were induced by a tail vein injection of recombinant adeno-associated virus (rAAV) encoding proprotein convertase subtilisin /kexin type 9 (PCSK9) and a high-fat diet for 12 weeks. ResultsUnexpectedly, mice with SMC-specific Ccl2 deletion developed higher levels of plasma cholesterol and larger atherosclerotic plaques with more macrophages compared with wild-type littermates. When total cholesterol levels were incorporated into the statistical analysis, none of the effects on plaque development between groups remained significant. Importantly, changes in plasma cholesterol and atherosclerosis remained in mice lacking Cre recombinase indicating that they were not caused by SMC-specific CCL2 deletion but by effects of the floxed allele or passenger genes. ConclusionsSMC-specific deficiency of Ccl2 does not significantly affect plaque development in hypercholesterolemic mice. Bullet pointsO_LISMCs express CCL2 in human plaques and upon inflammatory activation of a murine SMC line in vitro. C_LIO_LIDeletion of the Ccl2 gene in SMCs using Cre recombinase does not influence the size or composition of atherosclerotic plaque in mice. C_LIO_LIOnly by conducting a control study in mice without Cre recombinase was an initially observed difference in atherosclerosis concluded to be a genetic background effect. C_LI

pathology↗