Chen Yunfei, Peng Wei, Raffetto Joseph D, Khalil Raouf A
Vascular Surgery Research Laboratories, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
Vascular Surgery Research Laboratories, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
Prog Mol Biol Transl Sci. 2017;147:267-299. doi: 10.1016/bs.pmbts.2017.02.003. Epub 2017 Mar 21.
The veins of the lower extremity are equipped with efficient wall, contractile vascular smooth muscle (VSM), and competent valves in order to withstand the high venous hydrostatic pressure in the lower limb and allow unidirectional movement of deoxygenated blood toward the heart. The vein wall structure and function are in part regulated by matrix metalloproteinases (MMPs). MMPs are zinc-dependent endopeptidases that are secreted as inactive pro-MMPs by different cells in the venous wall including fibroblasts, VSM, and leukocytes. Pro-MMPs are activated by other MMPs, proteinases, and other endogenous and exogenous activators. MMPs degrade various extracellular matrix (ECM) proteins including collagen and elastin, and could affect other cellular processes including endothelium-mediated dilation, VSM cell migration, and proliferation as well as modulation of Ca signaling and contraction in VSM. It is thought that increased lower limb venous hydrostatic pressure increases hypoxia-inducible factors and other MMP inducers such as extracellular matrix metalloproteinase inducer, leading to increased MMP expression/activity, ECM protein degradation, vein wall relaxation, and venous dilation. Vein wall inflammation and leukocyte infiltration cause additional increases in MMPs, and further vein wall dilation and valve degradation, that could lead to chronic venous disease and varicose veins (VVs). VVs are often presented as vein wall dilation and tortuosity, incompetent venous valves, and venous reflux. Different regions of VVs show different MMP levels and ECM proteins with atrophic regions showing high MMP levels/activity and little ECM compared to hypertrophic regions with little or inactive MMPs and abundant ECM. Treatment of VVs includes compression stockings, venotonics, sclerotherapy, or surgical removal. However, these approaches do not treat the cause of VVs, and other lines of treatment may be needed. Modulation of endogenous tissue inhibitors of metalloproteinases (TIMPs), and exogenous synthetic MMP inhibitors may provide new approaches in the management of VVs.
下肢静脉具有有效的血管壁、可收缩的血管平滑肌（VSM）和功能正常的瓣膜，以承受下肢较高的静脉静水压力，并使脱氧血液单向流向心脏。静脉壁的结构和功能部分受基质金属蛋白酶（MMPs）调节。MMPs是锌依赖性内肽酶，由静脉壁中的不同细胞（包括成纤维细胞、VSM和白细胞）分泌为无活性的前MMPs。前MMPs被其他MMPs、蛋白酶以及其他内源性和外源性激活剂激活。MMPs降解包括胶原蛋白和弹性蛋白在内的各种细胞外基质（ECM）蛋白，并可能影响其他细胞过程，包括内皮介导的舒张、VSM细胞迁移和增殖，以及VSM中钙信号传导和收缩的调节。据认为，下肢静脉静水压力升高会增加缺氧诱导因子和其他MMP诱导剂，如细胞外基质金属蛋白酶诱导剂，导致MMP表达/活性增加、ECM蛋白降解、静脉壁松弛和静脉扩张。静脉壁炎症和白细胞浸润会导致MMPs进一步增加，进而导致静脉壁进一步扩张和瓣膜退化，这可能会导致慢性静脉疾病和静脉曲张（VVs）。VVs通常表现为静脉壁扩张和迂曲、静脉瓣膜功能不全以及静脉反流。VVs的不同区域显示出不同的MMP水平和ECM蛋白，与肥厚区域相比，萎缩区域显示出高MMP水平/活性且ECM较少，而肥厚区域的MMPs较少或无活性且ECM丰富。VVs的治疗方法包括穿弹力袜、使用静脉活性药物、硬化疗法或手术切除。然而，这些方法并未治疗VVs的病因，可能需要其他治疗方法。调节内源性金属蛋白酶组织抑制剂（TIMPs）和外源性合成MMP抑制剂可能为VVs的治疗提供新方法。
