Vascular endothelial growth factor receptor-1 modulates vascular endothelial growth factor-mediated angiogenesis via nitric oxide
Vascular endothelial growth factor receptor-1 modulates vascular endothelial growth factor-mediated angiogenesis via nitric oxide
复制标题
DOI：
10.1016/s0002-9440(10)61775-0
复制
发表时间：
2001-09-01
影响因子：
6
通讯作者：
Ahmed, A
中科院分区：
文献类型：
--
作者：
Bussolati, B;Dunk, C;Ahmed, A
血管内皮生长因子（VEGF）的已知反应是通过内皮细胞中的VEGF受体-2（VEGFR-2/KDR）介导的。然而，在生理或病理血管生成过程中，VEGFR-1（Flt-1）是VEGF的惰性诱饵还是信号受体尚不清楚。在这里，我们报告说，VEGF刺激的一氧化氮（NO）的释放被抑制的VEGFR-1和VEGFR-1通过NO负调节VEGFR-2介导的增殖，促进毛细血管网络的形成在人脐静脉内皮细胞（HUVEC）的封锁。在鼠基质胶血管生成测定中抑制VEGFR-1诱导大的血管生成素样结构。VEGF诱导的毛细血管生长在14天内被抗VEGFR-2阻断抗体抑制，如通过在体外血管生成测定中毛细血管连接之间的管长度减少（P < 0.0001）所确定的。相比之下，用中和抗VEGFR-1抗体使VEGFR-1活性丧失导致内皮细胞积累增加（P < 0.0001），并且通过加入NO供体而恢复的毛细血管连接数量急剧减少。表达人VEGFR-1但不表达VEGFR-2的猪主动脉内皮（PAE）细胞接种在生长因子减少的Matrigel上，重排成管状结构，这被抗VEGFR-1抗体或cGMP抑制剂阻止。VEGF刺激NO从VEGFR-1-但不是VEGFR-2转染的内皮细胞和胎盘生长因子-1刺激NO释放HUVEC。阻断VEGFR-1可增加VEGF介导的HUVEC增殖，这种增殖可被NO供体抑制，并可被NO合酶抑制剂增强。这些数据表明，VEGFR-1是一种信号受体，促进内皮细胞分化成血管管，部分通过限制VEGFR-2介导的内皮细胞增殖通过NO，这似乎是内皮细胞分化的分子开关。
The known responses of vascular endothelial growth factor (VEGF) are mediated through VEGF receptor-2 (VEGFR-2/KDR) in endothelial cells. However, it is unknown whether VEGFR-1 (Flt-1) is an inert decoy or a signaling receptor for VEGF during physiological or pathological angiogenesis. Here we report that VEGF-stimulated nitric oxide (NO) release is inhibited by blockade of VEGFR-1 and that VEGFR-1 via NO negatively regulates of VEGFR-2-mediated proliferation and promotes formation of capillary networks in human umbilical vein endothelial cells (HUVECs). Inhibition of VEGFR-1 in a murine Matrigel angiogenesis assay induced large aneurysm-like structures. VEGF-induced capillary growth over 14 days was inhibited by anti-VEGFR-2-blocking antibody as determined by reduced tube length between capillary connections (P < 0.0001) in an in vitro angiogenesis assay. In contrast, loss of VEGFR-1 activity with a neutralizing anti-VEGFR-1 antibody resulted in an increase in the accumulation of endothelial cells (P < 0.0001) and a dramatic decrease in the number of capillary connections that were restored by the addition of No donor. Porcine aortic endothelial (PAE) cells expressing human VEGFR-1 but not VEGFR-2 plated on growth factor-reduced Matrigel rearranged into tube-like structures that were prevented by anti-VEGFR-1 antibody or a cGMP inhibitor. VEGF stimulated NO release from VEGFR-1- but not VEGFR-2-transfected endothelial cells and placenta growth factor-1 stimulated NO release in HUVECs. Blockade of VEGFR-1 increased VEGF-mediated HUVEC proliferation that was inhibited by NO donors, and potentiated by NO synthase inhibitors. These data indicate that VEGFR-1 is a signaling receptor that promotes endothelial cell differentiation into vascular tubes, in part by limiting VEGFR-2-mediated endothelial cell proliferation via NO, which seems to be a molecular switch for endothelial cell differentiation.