Atherosclerotic 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 crucial source of collagens and that this impacts 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 affects advanced lesion formation given: 1) we previously identified a Col15a1 sequence variant associated with age related atherosclerosis; 2) COL15A1 is a matrix organizer enhancing tissue structural integrity; and 3) siRNA mediated Col15a1 knockdown increased migration and decreased proliferation of cultured human SMC. We hypothesized that SMC-derived COL15A1 is critical in advanced lesions, specifically in 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 specific Col15a1 knockout resulted in lesions reduced in size by 78%, with marked reductions in number and proliferating SMC, and lacked a SMC and ECM-rich lesion or fibrous cap. In vivo RNA-seq analyses on SMC Col15a1 knockout and wild type lesions suggest that a mechanism for these effects is through global repression of multiple pro-atherogenic inflammatory pathways involved in lesion development. These results provide the first direct evidence that a SMC-derived collagen, COL15A1, is critical during lesion pathogenesis but contrary to expectations, its loss resulted in marked attenuation rather than exacerbation of lesion pathogenesis.
- smooth muscle cells
- lineage tracing
- Copyright © 2017, American Journal of Physiology-Heart and Circulatory Physiology