Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
Dev Cell. 2012 Sep 11;23(3):600-10. doi: 10.1016/j.devcel.2012.07.015.
During angiogenesis, nascent vascular sprouts fuse to form vascular networks, enabling efficient circulation. Mechanisms that stabilize the vascular plexus are not well understood. Sphingosine 1-phosphate (S1P) is a blood-borne lipid mediator implicated in the regulation of vascular and immune systems. Here we describe a mechanism by which the G protein-coupled S1P receptor-1 (S1P1) stabilizes the primary vascular network. A gradient of S1P1 expression from the mature regions of the vascular network to the growing vascular front was observed. In the absence of endothelial S1P1, adherens junctions are destabilized, barrier function is breached, and flow is perturbed, resulting in abnormal vascular hypersprouting. Interestingly, S1P1 responds to S1P as well as laminar shear stress to transduce flow-mediated signaling in endothelial cells both in vitro and in vivo. These data demonstrate that blood flow and circulating S1P activate endothelial S1P1 to stabilize blood vessels in development and homeostasis.
在血管生成过程中，新生的血管芽融合形成血管网络，从而实现有效的循环。然而，稳定血管丛的机制还不是很清楚。鞘氨醇 1-磷酸（S1P）是一种血液传播的脂质介质，参与调节血管和免疫系统。在这里，我们描述了 G 蛋白偶联的 S1P 受体-1（S1P1）稳定原发性血管网络的机制。我们观察到，S1P1 的表达从血管网络的成熟区域到生长的血管前沿呈梯度分布。在没有内皮 S1P1 的情况下，黏附连接会不稳定，屏障功能会被破坏，血流会受到干扰，导致异常的血管过度发芽。有趣的是，S1P1 对 S1P 和层流剪切应力都有反应，从而在体外和体内的内皮细胞中传递血流介导的信号。这些数据表明，血流和循环中的 S1P 激活内皮 S1P1，以在发育和稳态中稳定血管。
