Abstract
Introduction: Current dogma states that under conditions that promote atherosclerosis quiescent vascular smooth muscle cells (SMC) phenotypically modulate into migratory, proliferative cells that move into the arterial intima, form a fibrous cap, and secrete extracellular matrix components (ECM) that promote plaque stabilization. However, there is no direct evidence that SMC derived ECM is critical in promoting changes to plaque stability. We identified collagen, type XV, alpha 1 (COL15A1) as a vascular SMC derived ECM protein present in both human and mouse atherosclerotic aortas. COL15A1 links large fibrillar collagens as well as promotes basement membrane cell adhesion and collagen maturation. We have shown in humans that Col15a1 is associated with atherosclerosis and is epigenetically regulated. However, the role for COL15A1 in atherosclerosis had not been explored. To assess the role of SMC derived collagen and COL15A1 in atherosclerosis we developed unique, conditional, tamoxifen inducible SMC specific Col15a1 knockout mice. We hypothesized that SMC production of COL15A1 is essential to promote indices of plaque stability. Methods and Results: At five weeks of age, SMC specific Col15a1fl/flApoE-/-MYH11-CreERT2+/- mice (n=15) and their Col15a1+/+ counterparts (n=12) were injected for 7 days with 1mg tamoxifen to induce SMC specific Col15a1 knockout and were placed on a Western diet (21% milk fat, 0.15% cholesterol) for 18 weeks. We find that SMC specific Col15a1 knockout induces marked detrimental changes in indices of plaque stability including increased necrotic core area (p=0.002), increased lesion size (p=0.03), and decreased plaque collagen maturation (p=0.017). Moreover, these mice showed a decrease in LGALS3+ macrophage content (p=0.008) but no change in SMC marker (ACTA2+) lesion staining. Conclusion: These data provide the first evidence that a SMC derived collagen (COL15A1) can positively affect indices of plaque stability and mediate plaque cellular content as well as identify COL15A1 as a novel player in atherosclerosis.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Arteriosclerosis, Thrombosis, and Vascular Biology
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
