Smooth muscle cell-specific deletion of Col15a1 unexpectedly leads to impaired development of advanced atherosclerotic lesions

Abstract

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 ) we have previously identified a sequence variant associated with age-related atherosclerosis, ) COL15A1 is a matrix organizer enhancing tissue structural integrity, and) small interfering RNA-mediated 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 knockout mice fed a Western diet for 18 wk failed to form advanced lesions. SMC-specific 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 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 knockout markedly attenuated advanced lesion formation, likely through reducing SMC proliferation and impairing multiple proatherogenic inflammatory processes.

Redox control of vascular smooth muscle cell function and plasticity

“…Indeed, recent SMC lineage tracing studies have demonstrated that SMC can become foam cell, mesenchymal stem cell, or myofibroblast-like in atherosclerosis, with these phenotypic states likely having both beneficial and detrimental effects on disease progression [9, 11, 14, 17]. It is reasonable to predict that similar observations will be made in other vascular diseases.…”

“…Notably, the advent of rigorous SMC lineage tracing mouse models has provided in vivo evidence that SMC phenotypic switching can occur in the context of disease and has greatly expanded upon this classic two-state contractile-synthetic model of SMC function. Specifically, these studies provide evidence that: (1) in vascular disease, SMC contractile genes, such as ACTA2, can be expressed by other cell types making lineage tracing essential for accurate identification of SMC in vivo [6–9]; (2) SMCs undergo oligoclonal proliferation in diseases, such as atherosclerosis and pulmonary arterial hypertension [10–15]; (3) in atherosclerosis, SMCs can express marker genes and take on functions ascribed to other cell types to become, for example, macrophage and/or myofibroblast like cells [12, 14, 16]; and (4) SMCs can have both beneficial and detrimental roles in atherosclerotic disease progression [11, 12, 17]. …”

Transcriptomics as Precision Medicine to Classify <em>In Vivo</em> Models of Dietary-Induced Atherosclerosis at Cellular and Molecular Levels

“…As (Apoe) null mice [14] and NZW rabbits [41], fed with high fat and high cholesterol diets [12,15]. This In summary, from our comparative transcriptome analysis, we discovered that both in vivo diet-induced models of coronary atherosclerosis, apolipoprotein E (Apoe) null mice [14] and NZW rabbits [41], share a substantial overlap in dysregulated biological processes, pathways, and molecules.…”

“…RNA-seq data used in this study were published (BioProject ID: PRJNA371776; [12]), and we used control mouse samples only (experiment IDs: SRX2544726, SRX2544727, SRX2544728). The following brief description of samples is from the original report [12].…”

“…RNA-seq data used in this study were published (BioProject ID: PRJNA371776; [12]), and we used control mouse samples only (experiment IDs: SRX2544726, SRX2544727, SRX2544728). The following brief description of samples is from the original report [12]. The male mice have mixed genetic background of C57BL/6J, C57BL/6N, 129S4 and FVB/N due to breeding in of multiple transgenes and floxed alleles, and their genotype is Col15a1 wt/wt , Myh11-CreER T2 , ROSA26-STOP flox -eYFP, Apoe -/-.…”