Matrix Metalloproteinase 9 (MMP-9) Regulates Vein Wall Biomechanics in Murine Thrombus Resolution

• Published in: PloS one Vol. 10; no. 9; p. e0139145
• Main Authors: Nguyen, Khanh P, McGilvray, Kirk C, Puttlitz, Christian M, Mukhopadhyay, Subhradip, Chabasse, Christine, Sarkar, Rajabrata
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.09.2015; Public Library of Science (PLoS)
• Subjects: Analysis; Angiogenesis; Animal models; Animals; Arteriosclerosis; Bioengineering; Biology; Biomechanical engineering; Biomechanical Phenomena; Biomechanics; Biomedical engineering; Blood clots; Bone marrow; Bone Marrow - pathology; Bone marrow transplantation; Bone mass; Care and treatment; Catheters; Clonal deletion; Collagen; Collagen - metabolism; Complications; Correlation analysis; Cytokines; Development and progression; Disease Models, Animal; Elastin; Elastin - metabolism; Experiments; Extracellular matrix; Extracellular Matrix - metabolism; Fibers; Gelatinase B; Gene Deletion; Genes; Genetic aspects; Immunohistochemistry; Immunology; Inflammation - pathology; Inflammatory diseases; Ischemia; Laboratory animals; Macrophages; Matrix metalloproteinase; Matrix Metalloproteinase 9 - metabolism; Matrix metalloproteinases; Mechanical engineering; Metalloproteinase; Mice; Modulus of elasticity; Neurosciences; Pain; Phenotypes; Risk factors; Stem cell transplantation; Stiffness; Thromboembolism; Thrombosis; Transplantation; Vascular diseases; Vascular surgery; Veins & arteries; Veins - enzymology; Veins - physiopathology; Venous Thrombosis - enzymology; Venous Thrombosis - physiopathology; California; United States > US; Colorado; Baltimore Maryland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0139145

Deep venous thrombosis is a common vascular problem with long-term complications including post-thrombotic syndrome. Post-thrombotic syndrome consists of leg pain, swelling and ulceration that is related to incomplete or maladaptive resolution of the venous thrombus as well as loss of compliance of the vein wall. We examine the role of metalloproteinase-9 (MMP-9), a gene important in extracellular remodeling in other vascular diseases, in mediating thrombus resolution and biomechanical changes of the vein wall. The effects of targeted deletion of MMP-9 were studied in an in vivo murine model of thrombus resolution using the FVB strain of mice. MMP-9 expression and activity significantly increased on day 3 after DVT. The lack of MMP-9 impaired thrombus resolution by 27% and this phenotype was rescued by the transplantation of wildtype bone marrow cells. Using novel biomechanical techniques, we demonstrated that the lack of MMP-9 significantly decreased thrombus-induced loss of vein wall compliance. Biomechanical analysis of the contribution of individual structural components showed that MMP-9 affected the elasticity of the extracellular matrix and collagen-elastin fibers. Biochemical and histological analyses correlated with these biomechanical effects as thrombi of mice lacking MMP-9 had significantly fewer macrophages and collagen as compared to those of wildtype mice. MMP-9 mediates thrombus-induced loss of vein wall compliance by increasing stiffness of the extracellular matrix and collagen-elastin fibers during thrombus resolution. MMP-9 also mediates macrophage and collagen content of the resolving thrombus and bone-marrow derived MMP-9 plays a role in resolution of thrombus mass. These disparate effects of MMP-9 on various aspects of thrombus illustrate the complexity of individual protease function on biomechanical and morphometric aspects of thrombus resolution.