title: Smooth muscle cell-specific deletion ofCol15a1unexpectedly 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 that1) we have previously identified aCol15a1sequence variant associated with age-related atherosclerosis,2) COL15A1 is a matrix organizer enhancing tissue structural integrity, and3) small interfering RNA-mediatedCol15a1knockdown 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-specificCol15a1knockout mice fed a Western diet for 18 wk failed to form advanced lesions. SMC-specificCol15a1knockout 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 SMCCol15a1knockout 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.NEW & NOTEWORTHYWe 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. SMCCol15a1knockout markedly attenuated advanced lesion formation, likely through reducing SMC proliferation and impairing multiple proatherogenic inflammatory processes.
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia.|Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia.
authors.forename: Brittany G
authors.initials: BG
authors.lastname: Durgin
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia.|Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Cherepanova
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia.|Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia.
authors.forename: Delphine
authors.initials: D
authors.lastname: Gomez
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia.
authors.forename: Themistoclis
authors.initials: T
authors.lastname: Karaoli
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia.|Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia.
authors.forename: Gabriel F
authors.initials: GF
authors.lastname: Alencar
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia.|Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Butcher
authors.affiliation: Department of Laboratory Medicine and Pathobiology, Ted Rogers Centre for Heart Research TBEP, University of Toronto, Toronto, Ontario, Canada; and.
authors.forename: Yu-Qing
authors.initials: YQ
authors.lastname: Zhou
authors.affiliation: Department of Laboratory Medicine and Pathobiology, Ted Rogers Centre for Heart Research TBEP, University of Toronto, Toronto, Ontario, Canada; and.
authors.forename: Michelle P
authors.initials: MP
authors.lastname: Bendeck
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia.|Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia.
authors.forename: Brant E
authors.initials: BE
authors.lastname: Isakson
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia.|Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Owens
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia; jessica.connelly@virginia.edu.|Department of Psychology, University of Virginia, Charlottesville, Virginia.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Connelly
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D001011:Aorta / Q000166:cytology; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology*; D019070:Cell Lineage; D003094:Collagen / Q000235:genetics*; D004036:Diet, Atherogenic; D005260:Female; D055785:Gene Knockdown Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000473:pathology*; D009213:Myography; D059289:Vascular Stiffness
chemical_list: C553732:collagen XV, mouse; D003094:Collagen
keywords: atherosclerosis; collagen; collagen type XV α1-gene; lineage tracing; smooth muscle cells