MacColl Elisabeth, Khalil Raouf A
Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.
Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts
J Pharmacol Exp Ther. 2015 Dec;355(3):410-28. doi: 10.1124/jpet.115.227330. Epub 2015 Aug 28.
Lower-extremity veins have efficient wall structure and function and competent valves that permit upward movement of deoxygenated blood toward 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 as inactive pro-MMPs by fibroblasts, vascular smooth muscle (VSM), and leukocytes. Pro-MMPs are activated by various activators including other MMPs and proteinases. 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, Ca(2+) signaling, and contraction. Increased lower-extremity hydrostatic venous pressure is thought to induce hypoxia-inducible factors and other MMP inducers/activators such as extracellular matrix metalloproteinase inducer, prostanoids, chymase, and hormones, leading to increased MMP 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 VV region (atrophic regions with little ECM versus hypertrophic regions with abundant ECM) and MMP form (inactive pro-MMP versus active MMP). Management of VVs includes compression stockings, venotonics, and surgical obliteration or removal. Because these approaches do not treat the causes of VVs, alternative methods are being developed. In addition to endogenous tissue inhibitors of MMPs, synthetic MMP inhibitors have been developed, and their effects in the treatment of VVs need to be examined.
下肢静脉具有高效的管壁结构和功能以及功能正常的瓣膜，这些瓣膜可使脱氧血液在静脉流体静压的作用下朝着心脏向上流动。基质金属蛋白酶（MMPs）在维持静脉壁结构和功能方面发挥着重要作用。MMPs是由成纤维细胞、血管平滑肌（VSM）和白细胞分泌的无活性前MMP形式的锌结合内肽酶。前MMPs可被包括其他MMPs和蛋白酶在内的多种激活剂激活。MMPs可导致细胞外基质（ECM）蛋白如胶原蛋白和弹性蛋白的降解，并且可能对内皮以及VSM细胞迁移、增殖、Ca(2+)信号传导和收缩产生额外影响。下肢静脉流体静压升高被认为会诱导缺氧诱导因子和其他MMP诱导剂/激活剂，如细胞外基质金属蛋白酶诱导剂、前列腺素、糜酶和激素，从而导致MMP表达/活性增加、ECM降解、VSM松弛和静脉扩张。白细胞浸润和静脉壁炎症会进一步导致MMPs增加、静脉壁扩张、瓣膜降解以及慢性静脉疾病（CVD）的不同临床阶段，包括静脉曲张（VVs）。VVs的特征是ECM失衡、瓣膜功能不全、静脉反流、管壁扩张和迂曲。VVs通常显示MMP水平升高，但根据VVs区域（ECM少的萎缩区域与ECM丰富的肥厚区域）和MMP形式（无活性前MMP与活性MMP），可能显示无变化或水平降低。VVs的治疗方法包括弹力袜、静脉活性药物以及手术闭塞或切除。由于这些方法并未治疗VVs的病因，因此正在开发替代方法。除了内源性MMP组织抑制剂外，已开发出合成MMP抑制剂，其在治疗VVs中的作用需要进行研究。
