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Research ArticleMinireviews

Matrix Metalloproteinases as Regulators of Vein Structure and Function: Implications in Chronic Venous Disease

Elisabeth MacColl and Raouf A. Khalil
Journal of Pharmacology and Experimental Therapeutics December 2015, 355 (3) 410-428; DOI: https://doi.org/10.1124/jpet.115.227330
Elisabeth MacColl
Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts
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Raouf A. Khalil
Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts
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Abstract

Lower-extremity veins have efficient wall structure and function and competent valves that permit upward movement of deoxygenated blood toward the heart against hydrostatic venous pressure. Matrix metalloproteinases (MMPs) play an important role in maintaining vein wall structure and function. MMPs are zinc-binding endopeptidases secreted as inactive pro-MMPs by fibroblasts, vascular smooth muscle (VSM), and leukocytes. Pro-MMPs are activated by various activators including other MMPs and proteinases. MMPs cause degradation of extracellular matrix (ECM) proteins such as collagen and elastin, and could have additional effects on the endothelium, as well as VSM cell migration, proliferation, Ca2+ signaling, and contraction. Increased lower-extremity hydrostatic venous pressure is thought to induce hypoxia-inducible factors and other MMP inducers/activators such as extracellular matrix metalloproteinase inducer, prostanoids, chymase, and hormones, leading to increased MMP expression/activity, ECM degradation, VSM relaxation, and venous dilation. Leukocyte infiltration and inflammation of the vein wall cause further increases in MMPs, vein wall dilation, valve degradation, and different clinical stages of chronic venous disease (CVD), including varicose veins (VVs). VVs are characterized by ECM imbalance, incompetent valves, venous reflux, wall dilation, and tortuosity. VVs often show increased MMP levels, but may show no change or decreased levels, depending on the VV region (atrophic regions with little ECM versus hypertrophic regions with abundant ECM) and MMP form (inactive pro-MMP versus active MMP). Management of VVs includes compression stockings, venotonics, and surgical obliteration or removal. Because these approaches do not treat the causes of VVs, alternative methods are being developed. In addition to endogenous tissue inhibitors of MMPs, synthetic MMP inhibitors have been developed, and their effects in the treatment of VVs need to be examined.

Footnotes

    • Received July 2, 2015.
    • Accepted August 27, 2015.
  • This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute (Grants HL-65998, HL-98724, and HL-111775). E.M. was a recipient of Summer Internship Funding from the Career Center at Hamilton College, Clinton, NY.

  • dx.doi.org/10.1124/jpet.115.227330.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 355 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 355, Issue 3
1 Dec 2015
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Research ArticleMinireviews

Matrix Metalloproteinases in Varicose Veins

Elisabeth MacColl and Raouf A. Khalil
Journal of Pharmacology and Experimental Therapeutics December 1, 2015, 355 (3) 410-428; DOI: https://doi.org/10.1124/jpet.115.227330

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Research ArticleMinireviews

Matrix Metalloproteinases in Varicose Veins

Elisabeth MacColl and Raouf A. Khalil
Journal of Pharmacology and Experimental Therapeutics December 1, 2015, 355 (3) 410-428; DOI: https://doi.org/10.1124/jpet.115.227330
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  • Article
    • Abstract
    • Introduction
    • MMP Structure
    • Pro- and Active MMPs
    • MMP Substrates
    • Tissue Distribution of MMPs
    • Chronic Venous Disease
    • Structural and Functional Abnormalities in VVs
    • MMP Levels in VVs
    • Venous Hydrostatic Pressure and MMPs in VVs
    • Inflammation and MMPs in VVs
    • Hypoxia and MMPs in VVs
    • Other Potential MMP Activators in VVs
    • Mechanisms of MMP Actions in VVs
    • MMPs and ECM Abnormalities in VVs
    • MMPs and VSM Dysfunction in VVs
    • MMPs and Endothelium-Dependent Relaxation
    • Management of VVs
    • TIMPs and TIMP/MMP Ratio
    • α2-Macroglobulin, Monoclonal Antibodies, and Other Endogenous MMP Inhibitors
    • Synthetic MMP Inhibitors
    • Venous versus Arterial MMPs
    • Perspectives
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
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