研究血管性血友病因子裂解酶抑制血管形成的机制

A Disintegrin-like And Metalloprotease with ThromboSpondin-1 repeats (ADAMTS)13 is a member of ADAMTS family. Proteolytic processing of von Willebrand factor (vWF) by ADAMTS13 metalloprotease is critical for maintaining normal hemostasis. This cleavage appears to be necessary to eliminate ultra large (UL)-vWF multimers in circulation, thereby preventing the formation of platelet-rich thrombi in small arterioles and capillaries. An inability to cleave newly synthesized and released UL- vWF from endothelial cells and megakaryocytes due to deficiency of plasma ADAMTS13 activity leads to a potentially fatal syndrome, thrombotic thrombocytopenic purpura (TTP). Recent studies have also suggested that ADAMTS13 deficiency may increase the risk of ischemic strokes and myocardial infarction, indicating that ADAMTS13 is a multifunctional protease. Previous study has been shown that ADAMTS1 and 8 inhibit angiogenesis, and the metalloprotease and TSP1 domain play important role. ADAMTS13 has similar structure and amino acid sequence with other members of ADAMTS family. Especially, ADAMTS13 has eight TSP1 domain which may play important role in angiogenesis. The purpose of this study is to indentify novel biological function of ADAMTS13- anti angiogenesis and study the mechanism.

血管性血友病因子裂解酶(ADAMTS13)属于ADAMTS 家族成员，通过降解超大分子血管性血友病因子多聚体（UL-vWF）抑制血小板聚集和微血管血栓的形成，从而维持正常的凝血状态。先天性和获得性ADAMTS13缺陷引起致命性综合症-血栓性血小板减少性紫癜（TTP）。近年研究表明，ADAMTS13还与心血管疾病的发生有关。表明ADAMTS13是一种具有多功能的金属蛋白酶。ADAMTS 家族成员中ADAMTS1和8具有抗血管形成功能,其金属蛋白酶结构域和I型血小板反应蛋白重复序列在抑制血管形成中起着重要作用。ADAMTS13和其它家族成员有着相似的结构和氨基酸序列,特别是ADAMTS13拥有8个I型血小板反应蛋白重复序列。本研究旨在探明ADAMTS13新的生物学功能-抗血管形成，并研究其作用机制。

血管性血友病因子裂解酶(ADAMTS13)属于ADAMTS 家族成员的金属蛋白酶，通过降解超大分子血管性血友病因子多聚体（UL-vWF）抑制血小板聚集和微血管血栓的形成，维持正常的凝血状态。先天性和获得性ADAMTS13缺陷引起致命性综合症-血栓性血小板减少性紫癜（TTP）。近年研究表明，ADAMTS13还与心血管疾病的发生有关。表明ADAMTS13是一种具有多功能的蛋白酶。ADAMTS家族成员中ADAMTS1,4和8具有抗血管形成功能,其金属蛋白酶结构域和I型血小板反应蛋白重复序列在抑制血管形成中起着重要作用。ADAMTS13和其它家族成员有着相似的结构和氨基酸序列,特别是ADAMTS13拥有8个I型血小板反应蛋白重复序列。通过体内外实验发现ADAMTS13对血管内皮细胞生长因子（VEGF）介导的新生血管形成的抑制作用。ADAMTS13对脐静脉内皮细胞（HUVEC）的增殖、分化、迁移能力均有抑制作用；对鸡胚绒毛尿囊膜和基质胶栓实验中提示ADAMTS13对血管形成有抑制作用。 ADAMTS13通过降低HUVECs的VEGFR磷酸,抑制HUVEC的增殖、分化、迁移能力。为抗肿瘤药物的研发提供新的方向。