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Learn MoreAtherosclerotic plaque rupture with subsequent embolic events is a major cause of sudden death from myocardial infarction or stroke. Although smooth muscle cells (SMC) produce and respond to collagens in vitro, there is no direct evidence in vivo that SMC are a critical source of collagens impacting lesion development or fibrous cap formation. We sought to determine how conditional SMC specific knockout of collagen type XV (COL15A1) in SMC lineage tracing mice effects advanced lesion formation. COL15A1 was chosen because: 1) we previously identified a Col15a1 sequence variant associated with age related atherosclerosis; 2) COL15A1 is a matrix organizer that enhances tissue structural integrity; and 3) siRNA mediated Col15a1 knockdown increased migration and decreased proliferation of SMC in vitro. We hypothesized that SMC derived COL15A1 is critical in advanced lesion pathogenesis and fibrous cap formation. Surprisingly, we demonstrate that SMC specific Col15a1 knockout mice fed a Western diet for 18 weeks failed to form advanced lesions. SMC Col15a1 knockout lesions have a drastic reduction in overall lesion size, cell accumulation, and the absence of a SMC and ECM- rich lesion or fibrous cap. In vivo RNA-seq analysis on lesions +/- SMC Col15a1 knockout suggests the mechanism for these effects is complex and associated with reductions in multiple pro-atherogenic inflammatory pathways in multiple cell types involved in lesion development. These results thus provide the first direct evidence that a SMC derived collagen is critical during lesion pathogenesis. Additionally, we conclude that SMC Col15a1 knockout unexpectedly inhibited rather than exacerbated lesion pathogenesis. SOURCE: Gary,K,Owens University of Virginia
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