PT  - JOURNAL ARTICLE
AU  - MacColl, Elisabeth
AU  - Khalil, Raouf A.
TI  - Matrix Metalloproteinases as Regulators of Vein Structure and Function. Implications in Chronic Venous Disease
AID  - 10.1124/jpet.115.227330
DP  - 2015 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.115.227330
4099  - http://jpet.aspetjournals.org/content/early/2015/08/28/jpet.115.227330.short
4100  - http://jpet.aspetjournals.org/content/early/2015/08/28/jpet.115.227330.full
AB  - Lower extremity veins have efficient wall structure and function and competent valves that permit upward movement of deoxygenated blood towards 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 by fibroblasts, vascular smooth muscle (VSM) and leukocytes as proMMPs, which are activated by other MMPs, proteinases and other activators. 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 EMMPRIN, prostanoids, chymase, and hormones, leading to increased MMPs 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 VVs region (atrophic vs. hypertrophic) and MMP form (pro- vs. active). Management of VVs includes compression stockings, venotonics, and surgical obliteration or removal. Because these approaches do not treat the cause of VVs, alternative methods are being developed. In addition to endogenous tissue inhibitors of MMPs (TIMPs), synthetic MMP inhibitors have been developed, and their effects in treatment of VVs need to be examined.