Tissue Inhibitor of Metalloproteinase is Increased in the Saphenofemoral Junction of Patients with Varicosities in the Leg

Abstract

Purpose: The goal of the present study was to examine the role of matrix metalloproteinase (MMP) activity in the development of varicose changes in the superficial veins of the lower extremity. Methods: Normal-caliber vein segments from the saphenofemoral junction were harvested from patients undergoing saphenous vein ligation for varices and from patients undergoing infrainguinal bypass graft procedures. The activity and quantity of MMPs and their inhibitors (tissue inhibitors of metalloproteinases [TIMPs]) in the vein segments were compared. Vein segments were obtained from 13 patients. Seven patients had varicose disease in the leg, including 6 women and 1 man (average age, 48 years). Six patients had no evidence of varicose disease, including 2 women and 4 men (average age, 59 years). Proteolytic activity was determined with substrate gel zymography, and enzyme content was determined with Western immunoblotting using monoclonal antibodies directed against MMP-2, MMP-3, MMP-9, TIMP-1, TIMP-2, and α 2 macroglobulin. Signals were quantified by scanning densitometry and normalized to a positive control (densitometric index [DI]). Immunohistochemistry was performed for enzyme localization. Results: Zymography did not detect a difference between groups at loci consistent with the major MMPs; however, a small but significant decrease in proteolytic activity was noted in veins from patients with varices. TIMP-1 is increased in vein segments from patients with varices (DI 0.8 ± 0.1 vs 0.2 ± 0.05, P < .05) while MMP-2 levels were decreased (DI 1.5 ± 0.3 vs 0.5 ± 0.1, P < .05). Immunohistochemistry localized MMPs to the adventitia of the vein wall. Conclusion: A decrease in proteolytic activity may be responsible for the histological and structural alterations leading to varicose degeneration of superficial lower extremity veins. (J Vasc Surg 1998;28:669-75.)