Abnormalities with Matrix Metalloproteinase Metabolism

Varicose veins have characteristically tortuous and dilated venous walls. A possible explanation for these findings may be the influences of proteolytic enzymes known as matrix metalloproteinases (MMPs) and their inhibitors known as tissue inhibitors of metalloproteinases (TIMPs), which lead to venous wall remodeling and subsequent dilatation and valvular incompetence. MMPs are highly homologous zinc-dependent endopeptidases that cleave most of the constituents of the extracellular matrix. To date there are 26 human MMPs that are classified according to their substrate specificity and structural similarities. The four major subgroups of MMPs are gelatinases, interstitial collagenases, strome-lysins, and membrane-type matrix metalloproteinases (MT-MMPs). MMPs are important enzymes in embryogenesis, acute tissue healing, remodeling, neoplastic invasion and metastasis, skin and granulomatous diseases, aging, and chronic wounds. MMPs are regulated by cytokines, growth factors, and activation of TIMP that specifically degrade and inactivate MMPs.

In the recent decade there has been a significant interest in the role of MMPs in the pathophysiology of varicose vein formation. An early report evaluating the collagen and elastin content of nonthrombophlebitic varicose veins compared to normal saphenous veins found that there was increased collagen and a significant decrease in elastin in both varicose veins and in the vein segment not affected by valvular incompetence but with varicosities at other sites. In this study gelatin zymography and elastase activity failed to demonstrate any differences, indicating the presence of an imbalance in tissue matrix but not attributable to proteolytic activity.4 In support of this prior study, evaluation of the vein segment at the saphenofemoral junction in patients with varicose veins demonstrated that MMPs activity was unchanged with that of control, with most of the MMPs located in the adventitia, and the content of MMP-2 was decreased but TIMP-1 content was increased.5 Neither of

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