Abstract Body (Do not enter title and authors here): Background
Smooth muscle cells (SMCs) are essential contributors in atherosclerosis. More than 50% of foam cells within the atherosclerotic lesions of mice or humans are from a SMC origin. SMCs can adopt several phenotypes in atherosclerosis which either increase the plaque stability or propagate atherosclerosis.
Membrane type-1 matrix metalloproteinase or MMP-14 is expressed in SMCs in atherosclerosis. However, whether this expression by SMCs is adaptive or pathogenic is unknown. A constitutive SMC-specific KO leads to aneurysm formation and worsens atherosclerosis. Here, we investigate the effect of inducible SMC-specific Mmp14 KO on mice cardiovascular function and on atherosclerosis development.
Methods
A tamoxifen-inducible SMC-specific Mmp14 KO is utilised under the control of Myh11Cre^ERT2. KO was induced in Myh11Cre^ERT2 Mmp14^f/f mice (Mmp14^SMCiKO), then, cardiac function was assessed using echocardiography, while vascular function was assessed using wire and pressure myography.
For atherosclerosis, Myh11Cre^ERT2 Mmp14^f/f Ldlr^-/- mice were fed Western Diet for 16-week. A comprehensive analysis of atherosclerotic lesions was done, and a single nuclei RNAseq analysis of aortas collected at the end point. Primary SMCs were isolated to investigate the possible mechanisms.
Results
Mmp14^SMCiKO has no significant effect on cardiac or vascular function. On the other hand, Ldlr^-/-/Mmp14^SMCiKO mice have significantly less atherosclerotic lesions (P<0.01) without aneurysm formation. Furthermore, Ldlr^-/-/Mmp14^SMCiKO lesions have higher collagen content (P<0.05). Sn-RNAseq analysis shows that SMCs in Ldlr^-/-/Mmp14^SMCiKO mice adopt a fibroblast ECM producing phenotype that increases plaque stability.
Primary SMCs isolated from the aorta of Mmp14^SMCiKO mice shows decreased ability to invade through a collagen type I barrier. Similarly, aortic Mmp14^SMCiKO SMC explant cultured in collagen type I gel is unable to degrade the surrounding collagen. Finally, primary SMCs lacking MMP14 were less proliferative.
Conclusion
Inducible SMC-specific Mmp14 KO did not affect the cardiovascular function, but significantly reduced atherosclerosis progression and increased the collagen content within Ldlr^-/- mice lesions.
Primary SMCs invasion, collagen degradation, and proliferation is significantly reduced in MMP14 KO. Understanding the molecular mechanisms of how MM14 modulates these processes will pave the way for possible therapeutic targets to ameliorate atherosclerosis development.