Abstract
Rationale: The matrix metalloproteinase (MMP) family plays diverse but critical role in the remodeling of collagen-rich extracellular matrix (ECM) environment in cardiovascular diseases. A membrane-type MMP, MMP14 (MT1-MMP) plays a key role in pericellular collagen remodeling. Despite the known role played by macrophage MMP14 in collagen remodeling of atheroma, the cell type-specific role of MMP14 in atherogenesis has not been fully defined. Objective: We aimed to define the consequence of whole-body MMP14 haploinsufficiency on atherogenesis and then determine the cell type that is responsible for MMP14-dependent modification of atherogenesis. Methods and Results: MMP14(+/-)ApoE(-/-) mice displayed a significant increase in atherogenesis in the whole arterial tree compared to MMP14(+/+)ApoE(-/-) mice (18.1±0.8 vs. 14.9±0.9% in males and 23.6±1.6 vs. 15.1±1.3% in females, P < 0.01). No difference in cholesterol level was found. When adipocyte MMP14 was deleted in aP2-Cre-ERT2/MMP14(f/f)/ApoE(-/-) mice (adipo-KO), profibrotic and proinflammatory changes in the visceral adipose tissue were observed; however, no significant effects on atherogenesis were noted (male Cre(-)/MMP14(f/f)/ApoE(-/-) control 8.5±1.5 vs. adipo-KO 4.6±1.5%, n = 4). On the other hand, the deletion of MMP14 from vascular smooth muscle cells (VSMCs) in SM22-Cre/MMP14(f/f)/ApoE(-/-) (VSMC-KO), markedly increased atherosclerotic area (male VSMC-KO 34.6±2.6%, P < 0.0001 compared to Cre(-) control, n = 11). The histology at aortic root after 8 weeks of Western diet demonstrates the significantly increased number of VSMCs with positive Ki67 staining coupled with the infiltration of F4/80-positive macrophages in VSMC-KO mice. Primary VSMCs isolated from VSMC-KO aortas displayed augmented stress fiber formation and increased proliferation capacity in vitro. Conclusions: MMP14 expressed in VSMCs plays a protective role against atherogenesis in ApoE-null mice. The loss of MMP14 causes the proliferative response of VSMCs in atherogenic conditions.
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