VEGF-C signaling pathways through VEGFR-2 and VEGFR-3 in vasculoangiogenesis and hematopoiesis.
VEGF-C signaling pathways through VEGFR-2 and VEGFR-3 in vasculoangiogenesis and hematopoiesis.
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DOI：
10.1182/blood.v96.12.3793
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发表时间：
2000-12
期刊：
影响因子：
20.3
通讯作者：
Koichi Hamada;Yuichi Oike;Nobuyuki Takakura;Yasuhiro Ito;L. Jussila;Daniel J. Dumont;Kari Alitalo-Kari-Alita
中科院分区：
文献类型：
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作者：
Koichi Hamada;Yuichi Oike;Nobuyuki Takakura;Yasuhiro Ito;L. Jussila;Daniel J. Dumont;Kari Alitalo-Kari-Alita
血管内皮生长因子(VEGFs)通过血管内皮生长因子受体(VEGFRs)传递信号，在血管发育和造血过程中发挥重要作用。采用小鼠腹主动脉旁内脏膜中胚层(P-Sp)与基质细胞共培养的方法，分析了VEGFR-2和VEGFR-3在血管生成和造血中的作用。血管生成和血管生成分别以血管床形成程度和网络形成程度来评价。在P-Sp培养中加入血管内皮生长因子-C可促进血管床的形成，并抑制最终的造血。加入可溶性VEGFR-1-Fc竞争蛋白可完全抑制血管床和网状结构的形成。在竞争对手在场的情况下，VEGF-C可以挽救血管床的形成，但不能挽救网络，而两者都可以被VEGF-A拯救。VEGFR-3基因缺陷的胚胎表现为血管系统异常和严重贫血。与体内发现一致的是，VEGFR-3缺陷胚胎的P-Sp中血管床的形成比野生型或杂合子胚胎中的血管床形成增强，并且造血受到严重抑制。在VEGFR-3基因缺陷胚胎的P-Sp培养中，加入VEGFR-3-Fc嵌合蛋白来捕获内源性VEGF-C，可抑制血管床的形成，部分挽救造血。这些结果表明，由于通过VEGFR-2传递的VEGFR-C信号与VEGFR-A协同作用，因此VEGFR-3与VEGFR-C的结合调节VEGFR-2信号转导。在VEGFR-3基因缺陷的胚胎中，VEGFR-2介导的过量的VEGFR-C信号导致胚胎发育过程中血管生成和造血功能的紊乱。这表明，通过VEGFR-3信号的精细调控在血管生成和造血中是至关重要的。(血。2000；96：3793-3800)
Signaling by vascular endothelial growth factors (VEGFs) through VEGF receptors (VEGFRs) plays important roles in vascular development and hematopoiesis. The authors analyzed the function of VEGF-C signaling through both VEGFR-2 and VEGFR-3 in vasculoangiogenesis and hematopoiesis using a coculture of para-aortic splanchnopleural mesoderm (P-Sp) explants from mouse embryos with stromal cells (OP9). Vasculogenesis and angiogenesis were evaluated by the extent of vascular bed and network formation, respectively. Addition of VEGF-C to the P-Sp culture enhanced vascular bed formation and suppressed definitive hematopoiesis. Both vascular bed and network formations were completely suppressed by addition of soluble VEGFR-1-Fc competitor protein. Formation of vascular beds but not networks could be rescued by VEGF-C in the presence of the competitor, while both were rescued by VEGF-A. VEGFR-3-deficient embryos show the abnormal vasculature and severe anemia. Consistent with these in vivo findings, vascular bed formation in the P-Sp from the VEGFR-3-deficient embryos was enhanced to that in wild-type or heterozygous embryos, and hematopoiesis was severely suppressed. When VEGFR-3-Fc chimeric protein was added to trap endogenous VEGF-C in the P-Sp culture of the VEGFR-3-deficient embryos, vascular bed formation was suppressed and hematopoiesis was partially rescued. These results demonstrate that because VEGF-C signaling through VEGFR-2 works synergistically with VEGF-A, the binding of VEGF-C to VEGFR-3 consequently regulates VEGFR-2 signaling. In VEGFR-3-deficient embryos, an excess of VEGF-C signals through VEGFR-2 induced the disturbance of vasculogenesis and hematopoiesis during embryogenesis. This indicates that elaborated control through VEGFR-3 signaling is critical in vasculoangiogenesis and hematopoiesis. (Blood. 2000;96:3793-3800)