Growth Differentiation Factor 6 Promotes Vascular Stability by Restraining Vascular Endothelial Growth Factor Signaling.
Growth Differentiation Factor 6 Promotes Vascular Stability by Restraining Vascular Endothelial Growth Factor Signaling.
复制标题
生长分化因子6通过限制血管内皮生长因子信号传导促进血管稳定性。
DOI：
10.1161/atvbaha.117.309571
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Weinstein BM
中科院分区：
文献类型：
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作者：
Krispin S;Stratman AN;Melick CH;Stan RV;Malinverno M;Gleklen J;Castranova D;Dejana E;Weinstein BM
功能血管系统的组装需要一个从激活到成熟的协调和动态的转变。高活性的血管内皮生长因子促进激活，包括连接失稳和细胞运动。成熟包括连接稳定和形成功能性内皮细胞屏障。促稳定信号的特性和作用机制大多仍不清楚。骨形态发生蛋白(BMP)受体及其配体在胚胎血管组装和成熟过程中具有重要作用。以前的研究已经表明骨形态发生因子6(BMP13)在血管完整性中的作用，尽管骨形态发生因子6的S的作用机制尚不清楚。因此，我们试图进一步探讨GDF6在血管稳定中的需求。我们研究了GDF6在斑马鱼体内和体外培养的人脐静脉内皮细胞(HUVEC)中促进内皮血管完整性的作用。我们报道，GDF6通过抑制血管内皮生长因子的活性来促进血管完整性。GDF6缺陷的内皮细胞增加了血管内皮生长因子信号转导，增加了VE-钙粘蛋白Y658的磷酸化，使VE-钙粘附素从细胞-细胞界面离位，并削弱了容易发生血管渗漏的内皮细胞黏附连接。我们的结果提示GDF6通过抑制血管内皮生长因子信号通路促进血管稳定。了解GDF6如何影响血管完整性可能有助于深入了解人类的出血和相关的血管病理。
The assembly of a functional vascular system requires a coordinated and dynamic transition from activation to maturation. High VEGF activity promotes activation, including junction destabilization and cell motility. Maturation involves junctional stabilization and formation of a functional endothelial barrier. The identity and mechanism of action of pro-stabilization signals is still mostly unknown. Bone morphogenetic protein (BMP) receptors and their ligands have important functions during embryonic vessel assembly and maturation. Previous work has suggested a role for GDF6 (BMP13) in vascular integrity, although GDF6’s mechanism of action was not clear. Therefore, we sought to further explore the requirement for GDF6 in vascular stabilization. We investigated the role of GDF6 in promoting endothelial vascular integrity in vivo in zebrafish and in cultured Human Umbilical Vein Endothelial Cells (HUVEC) in vitro. We report that GDF6 promotes vascular integrity by counteracting VEGF activity. GDF6-deficient endothelium has increased VEGF signaling, increased VE-cadherin Y658 phosphorylation, VE-cadherin delocalization from cell-cell interfaces, and weakened endothelial cell adherence junctions that become prone to vascular leak. Our results suggest that GDF6 promotes vascular stabilization by restraining VEGF signaling. Understanding how GDF6 affects vascular integrity may help to provide insights into hemorrhage and associated vascular pathologies in humans.