Proangiogenic Properties of Thrombospondin-4.
Proangiogenic Properties of Thrombospondin-4.
复制标题
血小板传播-4的促血管生成特性。
DOI：
10.1161/atvbaha.115.305912
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发表时间：
2015-09
期刊：
影响因子：
--
通讯作者：
Stenina-Adognravi O
中科院分区：
文献类型：
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作者：
Muppala S;Frolova E;Xiao R;Krukovets I;Yoon S;Hoppe G;Vasanji A;Plow E;Stenina-Adognravi O
凝血酶敏感蛋白-4(TSP-4)是凝血酶敏感蛋白家族5个成员之一。TSP-1和TSP-2是有效的抗血管生成蛋白。然而，另外3个不包含TSP-1和TSP-2抗血管生成活性的结构域的TSP的血管生成特性还没有被探索。我们在前期的研究中发现，TSP-4在不同大小的血管基质中均有表达，在毛细血管中尤其丰富。我们试图确定TSP-4在血管生成调控中的作用。利用Thbs4−/−；小鼠、来源于这些小鼠的内皮细胞(EC)和重组TSP-4来评估TSP-4在体内血管生成模型中的作用及其对培养细胞中血管生成相关特性的影响。与野生型小鼠相比，Thbs4−/−；小鼠的血管生成减少。生长血管的管腔内可见TSP-4的表达。与A387相比，表达P387TSP-4变体的小鼠表现出更大的血管生成。P387TSP-4变体以前与冠状动脉疾病有关，并被发现在细胞相互作用中更活跃。小鼠肺内皮细胞的黏附、迁移和增殖能力较野生型小鼠肺内皮细胞的黏附、迁移和增殖能力降低。重组TSP-4可促进EC的增殖和迁移。整合素和加巴喷丁α2受体α2δ-1是参与TSP-4调控EC黏附、迁移和增殖的受体。TSP-4是一种细胞外基质蛋白，以前与组织重塑有关，现在被证明具有促血管生成活性。
Thrombospondin-4 (TSP-4) is 1 of the 5 members of the thrombospondin protein family. TSP-1 and TSP-2 are potent antiangiogenic proteins. However, angiogenic properties of the 3 other TSPs, which do not contain the domains associated with the antiangiogeneic activity of TSP-1 and TSP-2, have not been explored. In our previous studies, we found that TSP-4 is expressed in the vascular matrix of blood vessels of various sizes and is especially abundant in capillaries. We sought to identify the function of TSP-4 in the regulation of angiogenesis. The effect of TSP-4 in in vivo angiogenesis models and its effect on angiogenesis-related properties in cultured cells were assessed using Thbs4−/−; mice, endothelial cells (EC) derived from these mice, and recombinant TSP-4. Angiogenesis was decreased in Thbs4−/−; mice compared with wild-type mice. TSP-4 was detected in the lumen of the growing blood vessels. Mice expressing the P387 TSP-4 variant, which was previously associated with coronary artery disease and found to be more active in its cellular interactions, displayed greater angiogenesis compared with A387 form. Lung EC from Thbs4−/−; mice exhibited decreased adhesion, migration, and proliferation capacities compared with EC from wild-type mice. Recombinant TSP-4 promoted proliferation and the migration of EC. Integrin and gabapentin α2 receptor α2δ-1 were identified as receptors involved in regulation of EC adhesion, migration, and proliferation by TSP-4. TSP-4, an extracellular matrix protein previously associated with tissue remodeling, is now demonstrated to possess proangiogenic activity.