Biological characterization of angiopoietin-3 and angiopoietin-4
Biological characterization of angiopoietin-3 and angiopoietin-4
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DOI：
10.1096/fj.03-1466com
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发表时间：
2004-08-01
期刊：
影响因子：
4.8
通讯作者：
Koh, GY
中科院分区：
文献类型：
--
作者：
Lee, HJ;Cho, CH;Koh, GY
血管生成素（Ang）家族的生长因子包括Ang 1、Ang 2、Ang 3和Ang 4，所有这些都与内皮受体酪氨酸激酶Tie 2结合。Ang 3（小鼠）和Ang 4（人）是种间直系同源物。在人内皮细胞系的实验中，Ang 3被鉴定为Tie 2的拮抗剂，Ang 4被鉴定为Tie 2的激动剂。然而，Ang 3和Ang 4的生物学作用尚不清楚。我们研究了重组Ang 3和Ang 4蛋白在原代培养的内皮细胞和小鼠体内的生物学效应。重组Ang 3和Ang 4形成二硫键连接的二聚体。Ang 4（400 ng/mL）显著增加原代培养的HUVECs中Tie 2和Akt磷酸化，而Ang 3（400 ng/mL）没有产生显著变化。因此，Ang 4而不是Ang 3诱导原代培养的HUVEC的存活和迁移。出乎意料的是，静脉内施用的Ang 3（30 μ g）在体内磷酸化来自小鼠的肺组织中的Tie 2受体方面比Ang 4（30 μ g）更有效。因此，在原代培养的小鼠肺微血管内皮细胞中，Ang 3比Ang 4更有效地磷酸化Akt。Ang 3和Ang 4均在体内产生从利姆布斯延伸穿过小鼠角膜的有效角膜血管生成。因此，Ang 3和Ang 4是Tie 2的激动剂，但小鼠Ang 3仅对其自身物种的内皮细胞具有强活性。
The angiopoietin (Ang) family of growth factors includes Ang1, Ang2, Ang3, and Ang4, all of which bind to the endothelial receptor tyrosine kinase Tie2. Ang3 ( mouse) and Ang4 ( human) are interspecies orthologs. In experiments with human endothelial cell lines, Ang3 was identified as an antagonist of Tie2 and Ang4 was identified as an agonist of Tie2. However, the biological roles of Ang3 and Ang4 are unknown. We examined the biological effect of recombinant Ang3 and Ang4 proteins in primary cultured endothelial cells and in vivo in mice. Recombinant Ang3 and Ang4 formed disulfide-linked dimers. Ang4 ( 400 ng/mL) markedly increased Tie2 and Akt phosphorylation in primary cultured HUVECs whereas Ang3 ( 400 ng/mL) did not produce significant changes. Accordingly, Ang4, but not Ang3, induced survival and migration in primary cultured HUVECs. Unexpectedly, intravenously administered Ang3 ( 30 mug) was more potent than Ang4 ( 30 mug) in phosphorylating the Tie2 receptor in lung tissue from mice in vivo. Accordingly, Ang3 was more potent than Ang4 in phosphorylating Akt in primary cultured mouse lung microvascular endothelial cells. Ang3 and Ang4 both produced potent corneal angiogenesis extending from the limbus across the mouse cornea in vivo. Thus, Ang3 and Ang4 are agonists of Tie2, but mouse Ang3 has strong activity only on endothelial cells of its own species.