Department of Pediatrics and Developmental Vascular Biology Program, Medical College of Wisconsin and Children's Research Institute, Milwaukee, WI 53226, USA.
Blood. 2010 Jun 3;115(22):4614-22. doi: 10.1182/blood-2009-10-248856. Epub 2010 Jan 19.
Endothelial cell-specific chemotaxis receptor (ECSCR) is a cell surface protein expressed by blood endothelial cells with roles in endothelial cell migration and signal transduction. We investigated the function of ecscr in the development of the zebrafish vasculature. Zebrafish ecscr is expressed in angioblasts and in axial vessels during angioblast migration and vasculogenesis. Morpholino-directed ecscr knockdown resulted in defective angioblast migration in the posterior lateral plate mesoderm, a process known to depend on vascular endothelial-derived growth factor (VEGF). In cultured cells, transfected ECSCR localized to actin-rich membrane protrusions, colocalizing with kinase insert domain protein receptor (KDR)/VEGF receptor 2 in these regions. ECSCR-silenced cells show reduced VEGF-induced phosphorylation of KDR but not of FMS-like tyrosine kinase 1 (FLT1)/VEGF receptor 1. Finally, chemical inhibition of VEGF receptor activity in zebrafish resulted in angioblast deficiencies that partially overlap with those seen in ecscr morphants. We propose that ecscr promotes migration of zebrafish angioblasts by enhancing endothelial kdr sensitivity to VEGF.
内皮细胞特异性趋化因子受体 (ECSCR) 是一种表达在血液内皮细胞表面的蛋白，在内皮细胞迁移和信号转导中发挥作用。我们研究了 ecscr 在斑马鱼血管发育中的功能。斑马鱼 ecscr 在血管母细胞瘤和血管生成过程中的轴向血管中表达。针对 ecscr 的 morpholino 引导的敲低导致在后侧板中胚层的血管母细胞瘤迁移缺陷，已知该过程依赖于血管内皮衍生的生长因子 (VEGF)。在培养的细胞中，转染的 ECSCR 定位于富含肌动蛋白的膜突起，与这些区域中的激酶插入结构域蛋白受体 (KDR)/VEGF 受体 2 共定位。ECSCR 沉默的细胞显示出 VEGF 诱导的 KDR 磷酸化减少，但 FMS 样酪氨酸激酶 1 (FLT1)/VEGF 受体 1 的磷酸化没有减少。最后，在斑马鱼中化学抑制 VEGF 受体活性导致血管母细胞瘤缺陷，与 ecscr 形态发生缺陷部分重叠。我们提出，ecscr 通过增强内皮细胞 kdr 对 VEGF 的敏感性来促进斑马鱼血管母细胞瘤的迁移。
