Conditional knockout of membrane-type I matrix metalloproteinase in smooth muscle cells of adult mice alleviates atherosclerosis without affecting basic cardiovascular function

Abstract

Background: Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality worldwide. Despite effective lipid-lowering treatments, substantial residual risks remain. In atherosclerosis, vascular smooth muscle cells (SMCs) undergo dedifferentiation, promoting disease progression. Membrane-type I matrix metalloproteinase (MT1-MMP/MMP14) promotes SMC dedifferentiation. However, the effect of inhibiting MMP14 in adults, particularly those with existing atherosclerotic plaques, is unclear.

Methods: We developed an inducible conditional SMC-specific MMP14 knockout mouse model. Cardiac and vascular function were assessed using echocardiography and wire myography, respectively. Atherosclerosis progression and regression were evaluated in Ldlr^−/− mice with or without MMP14 deficiency. snRNA-seq of the aortas from Ldlr^−/− mice was performed to determine the effect on SMC populations.

Results: MMP14 expression was elevated in SMCs within fibroatheroma compared with the pathological intima thickening in coronary aortas from patients with ASCVD. Conditional knockout of SMC MMP14 in adult mice did not change plasma cholesterol levels or basic cardiac and vascular function. However, atherosclerosis development was reduced, and the regression of existing plaques was enhanced in Ldlr^−/− mice lacking SMC MMP14. snRNA-seq revealed increased fibroblast-like SMCs and reduced foam cell-like SMCs in MMP14-deficient Ldlr^−/− mice compared to Ldlr^−/− mice. Furthermore, SMC MMP14 deficiency decreased SMC proliferation and migration, accompanied by reduced platelet-derived growth factor receptor (PDGFR) β levels and attenuated PDGF signalling.

Conclusion: SMC MMP14 promotes atherosclerosis in adult mice, likely through reducing PDGF signalling and inhibiting SMC migration and proliferation.

Keywords

atherosclerosis / cardiovascular disease / cell dedifferentiation / MMP14 / PDGF signalling / smooth muscle cell

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