Vascular Surgery Research Laboratory, Division of Vascular and Endovascular Surgery, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA 02115, USA.
Curr Drug Targets. 2013 Mar;14(3):287-324.
Varicose veins (VVs) are a common venous disease of the lower extremity characterized by incompetent valves, venous reflux, and dilated and tortuous veins. If untreated, VVs could lead to venous thrombosis, thrombophlebitis and chronic venous leg ulcers. Various genetic, hormonal and environmental factors may lead to structural changes in the vein valves and make them incompetent, leading to venous reflux, increased venous pressure and vein wall dilation. Prolonged increases in venous pressure and vein wall tension are thought to increase the expression/activity of matrix metalloproteinases (MMPs). Members of the MMPs family include collagenases, gelatinases, stromelysins, matrilysins, membrane- type MMPs and others. MMPs are known to degrade various components of the extracellular matrix (ECM). MMPs may also affect the endothelium and vascular smooth muscle, causing changes in the vein relaxation and contraction mechanisms. Endothelial cell injury also triggers leukocyte infiltration, activation and inflammation, which lead to further vein wall damage. The vein wall dilation and valve dysfunction, and the MMP activation and superimposed inflammation and fibrosis would lead to progressive venous dilation and VVs formation. Surgical ablation is an effective treatment for VVs, but may be associated with high recurrence rate, and other less invasive approaches that target the cause of the disease are needed. MMP inhibitors including endogenous tissue inhibitors (TIMPs) and pharmacological inhibitors such as zinc chelators, doxycycline, batimastat and marimastat, have been used as diagnostic and therapeutic tools in cancer, autoimmune and cardiovascular disease. However, MMP inhibitors may have side effects especially on the musculoskeletal system. With the advent of new genetic and pharmacological tools, specific MMP inhibitors with fewer undesirable effects could be useful to retard the progression and prevent the recurrence of VVs.
静脉曲张（VVs）是一种常见的下肢静脉疾病，其特征为瓣膜功能不全、静脉反流和扩张扭曲的静脉。如果不治疗，VVs 可能导致静脉血栓形成、血栓性静脉炎和慢性静脉腿部溃疡。各种遗传、激素和环境因素可能导致静脉瓣膜结构改变，使其功能不全，导致静脉反流、静脉压升高和静脉壁扩张。静脉压和静脉壁张力的持续升高被认为会增加基质金属蛋白酶（MMPs）的表达/活性。MMPs 家族成员包括胶原酶、明胶酶、基质溶解素、基质金属蛋白酶和其他类型。MMPs 已知可降解细胞外基质（ECM）的各种成分。MMPs 还可能影响内皮细胞和血管平滑肌，导致静脉松弛和收缩机制发生变化。内皮细胞损伤还会引发白细胞浸润、激活和炎症，导致进一步的静脉壁损伤。静脉壁扩张和瓣膜功能障碍，以及 MMP 激活和叠加的炎症和纤维化，会导致静脉进行性扩张和 VVs 形成。手术消融是 VVs 的有效治疗方法，但可能与高复发率相关，需要针对疾病原因的其他微创方法。基质金属蛋白酶抑制剂，包括内源性组织抑制剂（TIMPs）和药理学抑制剂，如锌螯合剂、强力霉素、巴曲酶和马立司他，已被用作癌症、自身免疫和心血管疾病的诊断和治疗工具。然而，基质金属蛋白酶抑制剂可能有副作用，尤其是对肌肉骨骼系统。随着新的遗传和药理学工具的出现，具有较少不良作用的特异性 MMP 抑制剂可能有助于延缓进展并预防 VVs 的复发。
