Related Experiment Video
Updated: May 6, 2026
Murine Aortic Crush Injury: An Efficient In Vivo Model of Smooth Muscle Cell Proliferation and Endothelial Function
Published on: June 11, 2017
Matrix metalloproteinase-8 promotes vascular smooth muscle cell proliferation and neointima formation
Qingzhong Xiao1, Feng Zhang, Gianluca Grassia
1From William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom (Q. Xiao, F.Z., S.Y.); Department of Cardiology, Peking University People's Hospital, Beijing, China (F.Z.); Department of Pharmacy, University of Naples Federico II, Naples, Italy (G.G., M. Maddaluno, P.M., A.I.); Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (Y.H., Z.Z., Q. Xing, X.Y., M. Mayr, Q. Xu); Clemens Schöpf Institute, Technische Universität Darmstadt, Darmstadt, Germany (B.D., B.S.); Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom (P.M.).
Objective:
We investigated the role of matrix metalloproteinase-8 (MMP8) in neointima formation and in vascular smooth muscle cell (VSMC) migration and proliferation.
Approach And Results:
After carotid artery wire injuring, MMP8(-/-)/apoE(-/-) mice had fewer proliferating cells in neointimal lesions and smaller lesion sizes. Ex vivo assays comparing VSMCs isolated from MMP8 knockout and wild-type mice showed that MMP8 knockout decreased proliferation and migration. Proteomics analysis revealed that a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) had lower concentrations in MMP8 knockout VSMC culture media than in MMP8 wild-type VSMC culture media. Western blot, flow cytometric, and immunocytochemical analyses showed that MMP8 knockout VSMCs contained more pro-ADAM10 but less mature ADAM10, more N-cadherin, and β-catenin in the plasma membrane but less β-catenin in the nucleus and less cyclin D1. Treatment of MMP8 wild-type VSMCs with an ADAM10 inhibitor, GI254023X, or siRNA knockdown of ADAM10 in MMP8 wild-type VSMCs inhibited proliferation and migration, increased N-cadherin and β-catenin in the plasma membrane, reduced β-catenin in the nucleus, and decreased cyclin D1 expression. Incubation of MMP8 knockout VSMCs with a recombinant ADAM10 rescued the proliferative and migratory ability of MMP8 knockout VSMCs and increased cyclin D1 expression. Furthermore, immunohistochemical analyses showed colocalization of ADAM10 with VSMCs and N-cadherin, and nuclear accumulation of β-catenin in the neointima in apoE(-/-)/MMP8(+/+) mice.
Conclusions:
MMP8 enhances VSMC proliferation via an ADAM10, N-cadherin, and β-catenin-mediated pathway and plays an important role in neointima formation.
Insights
Matrix metalloproteinase-8 (MMP8) promotes vascular smooth muscle cell (VSMC) proliferation and migration, impacting neointima formation. Inhibiting MMP8 or its downstream targets reduces these effects.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Cell Biology
Background:
- Neointima formation is a key process in atherosclerosis and restenosis after vascular injury.
- Matrix metalloproteinases (MMPs) are implicated in extracellular matrix remodeling and cell migration.
- The specific role of matrix metalloproteinase-8 (MMP8) in vascular smooth muscle cell (VSMC) behavior and neointima formation requires elucidation.
Purpose of the Study:
- To investigate the role of MMP8 in neointima formation.
- To determine the effect of MMP8 on VSMC migration and proliferation.
- To elucidate the molecular mechanisms by which MMP8 influences VSMC behavior.
Main Methods:
- Carotid artery wire injury model in MMP8 knockout and wild-type mice.
- Ex vivo proliferation and migration assays using isolated VSMCs.
- Proteomics, Western blot, flow cytometry, and immunocytochemistry to analyze protein expression and localization.
- Inhibition and knockdown studies targeting ADAM10.
- Recombinant ADAM10 rescue experiments.
Main Results:
- MMP8 knockout mice exhibited reduced neointima formation, fewer proliferating cells, and smaller lesion sizes.
- MMP8 deficiency decreased VSMC proliferation and migration in vitro.
- MMP8 knockout VSMCs showed altered expression of ADAM10, N-cadherin, and β-catenin.
- ADAM10 inhibition or knockdown mimicked the effects of MMP8 deficiency on VSMC proliferation and migration.
- Recombinant ADAM10 rescued the impaired proliferation and migration of MMP8 knockout VSMCs.
Conclusions:
- MMP8 plays a significant role in neointima formation.
- MMP8 enhances VSMC proliferation and migration through a pathway involving ADAM10, N-cadherin, and β-catenin.
- Targeting MMP8 or its downstream effectors may represent a therapeutic strategy for preventing neointima formation.
More Related Videos
08:43Calcification of Vascular Smooth Muscle Cells and Imaging of Aortic Calcification and Inflammation
Published on: May 31, 2016
08:28Isolation of Primary Patient-specific Aortic Smooth Muscle Cells and Semiquantitative Real-time Contraction Measurements In Vitro
Published on: February 15, 2022
Related Concept Videos
01:24Regulation of Angiogenesis and Blood Supply
01:10Mechanism of Angiogenesis
01:23Role of Matrix Metalloproteases in Degradation of ECM
01:30Atherosclerosis I: Introduction