Collagen alpha-1(XV) chain precursor [Contains: Restin (Endostatin-XV) (Related to endostatin) (Restin-I); Restin-2 (Restin-II); Restin-3 (Restin-III); Restin-4 (Restin-IV)]
Atherosclerotic plaque rupture with subsequent embolic events is a major cause of sudden death from myocardial infarction or stroke. Although smooth muscle cells (SMCs) produce and respond to collagens in vitro, there is no direct evidence in vivo that SMCs 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 that [i]1[/i]) we have previously identified a [i]Col15a1[/i] sequence variant associated with age-related atherosclerosis, [i]2[/i]) COL15A1 is a matrix organizer enhancing tissue structural integrity, and [i]3[/i]) small interfering RNA-mediated [i]Col15a1[/i] knockdown increased migration and decreased proliferation of cultured human SMCs. We hypothesized that SMC-derived COL15A1 is critical in advanced lesions, specifically in fibrous cap formation. Surprisingly, we demonstrated that SMC-specific [i]Col15a1[/i] knockout mice fed a Western diet for 18 wk failed to form advanced lesions. SMC-specific [i]Col15a1[/i] knockout resulted in lesions reduced in size by 78%, with marked reductions in numbers and proliferating SMCs, and lacked a SMC and extracellular matrix-rich lesion or fibrous cap. In vivo RNA-seq analyses on SMC [i]Col15a1[/i] knockout and wild-type lesions suggested that a mechanism for these effects is through global repression of multiple proatherogenic 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. We report the first direct in vivo evidence that a smooth muscle cell (SMC)-produced collagen, collagen type XV (COL15A1), is critical for atherosclerotic lesion development. SMC [i]Col15a1[/i] knockout markedly attenuated advanced lesion formation, likely through reducing SMC proliferation and impairing multiple proatherogenic inflammatory processes.
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