Abstract
ObjectiveDeep 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.Methods and ResultsThe 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.ConclusionsMMP-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.
Highlights
The biology of venous thrombus resolution plays a central role in a number of significant cardiovascular diseases
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 macrophage and collagen content of the resolving thrombus and bone-marrow derived MMP-9 plays a role in resolution of thrombus mass
Summary
The biology of venous thrombus resolution plays a central role in a number of significant cardiovascular diseases. Deep venous thrombosis (DVT) is an exceedingly common and serious problem with between 350,000 to 600,000 cases annually in the U.S and 200,000 deaths from pulmonary embolism (PE) [1]. The acute mortality of PE can be effectively prevented by early diagnosis of DVT and prompt anticoagulation. Despite anticoagulation, post-thrombotic syndrome develops in 20–60% of patients within months to years after initial DVT [1]. Post-thrombotic syndrome consists of pain, swelling and skin ulceration that impair daily activities, prevent employment and lower quality of life. Patients with more rapid spontaneous thrombus resolution of DVT have less subsequent venous reflux [2], suggesting that the process of thrombus resolution (or failure thereof) is central to the pathogenesis of post-thrombotic syndrome
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