Metalloprotease-Dependent Fibrinolysis and Angiogenesis

描述：在与生理和病理状态相关的新生血管形成过程中，多种生长因子启动血管生成反应，诱导内皮细胞穿过其下层基膜并浸润周围的间质基质。然后胶原纤维蛋白基质作为进入血管的基质。同时，血管生成生长因子，如VEGF，单独或与其他生长因子联合作用，调节内皮细胞粘附分子和蛋白酶的表达，使细胞穿透胶原/纤维蛋白屏障，并经历一个小管生成程序。虽然一系列抗血管生成疗法在动物模型中，甚至在人类中，已经显示出与肿瘤发生/转移以及炎症相关的疾病状态有希望的效果，但对于在病理部位调节新血管发育的蛋白酶的身份，或调节其表达的因素，我们知之甚少。事实上，尽管许多胶原溶解和纤维蛋白溶解级联被认为在血管生成中起关键作用，但我们最近发现了一个小家族的膜锚定金属蛋白酶，似乎在驱动血管形成中起主导作用。基于支持MT1-MMP在基底膜侵袭、内皮细胞侵袭和增殖以及形态发生中的作用的新发现，我们建议：1)确定MT1-MMP在内皮细胞介导的基底膜降解和穿孔中的作用，ii)表征MT1-MMP在体内血管生成过程中基底膜更新中的作用，iii)确定内皮细胞MT1-MMP的生长调节特性。iv)表征调节新血管形成的MT1-MMP的形态诱导特性；v)比较和对比淋巴内皮动员的驱动侵袭、增殖和分支小管形成的蛋白水解机制。总之，概述的研究应该有助于建立蛋白酶在生理和病理状态下调节新血管生长的基本机制，并可能有助于确定新的干预靶点。

DESCRIPTION: During the neovascularization process associated with physiologic as well as pathologic states, a variety of growth factors initiate an angiogenic response which induces endothelial cells to cross their underlying basement membrane and to infiltrate the surrounding interstitial matrix. The collagen-fibrin matrix then acts as a substratum for ingressing blood vessels. Concurrently, angiogenic growth factors such as VEGF, working alone or in combination with other growth factors, regulates the expression of endothelial cell adhesion molecules and proteinases which allow the cells to penetrate collagen/fibrin barriers, and undergo a tubulogenic program. While a range of anti-angiogenic therapeutics have shown promising effects in animal models - and even in humans - with regard to disease states associated with tumorigenesis/metastasis as well as inflammation, little is known with regard either to the identity of the proteinases that regulate the development of neovessels at pathologic sites, or the factors that regulate their expression. Indeed, whereas a number of collagenolytic and fibrinolytic cascades have been posited to play a critical role in angiogenesis, we have recently identified a small family of membrane-anchored metalloproteinases that appear to play a dominant role in driving blood vessel formation. Based on new findings which support a role for MT1-MMP in basement membrane invasion, endothelial cell invasion and proliferation as well as morphogenesis, we propose to i) Define the role of MT1-MMP in endothelial cell-mediated basement membrane degradation and perforation, ii) characterize the role of MT1-MMP in basement membrane turnover during in vivo angiogenesis, iii) define the growth regulatory properties of endothelial cell MT1-MMP, iv) characterize the morphogen-inducing properties of MT1-MMP that regulate neovessel formation and v) compare and contrast the proteolytic machinery mobilized by lymphatic endothelium that drive invasion, proliferation and branching tubulogenesis. Together, the outlined studies should help establish the basic mechanisms by which proteinases regulate neovessel growth during physiologic as well as pathologic states, and may assist in the identification of new targets for intervention.