The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching
The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching
复制标题
DOI：
10.1073/pnas.0611177104
复制
发表时间：
2007-02-27
影响因子：
11.1
通讯作者：
Eichmann, Anne
中科院分区：
文献类型：
--
作者：
Suchting, Steven;Freitas, Catarina;Eichmann, Anne
Delta样4（Dll 4）是Notch受体的跨膜配体，其在动脉血管和萌芽内皮细胞中表达。在这里，我们表明，Dll 4调节血管分支在发展过程中，通过抑制内皮细胞形成。dll 4的杂合性缺失或使用γ-分泌酶抑制剂的Notch信号传导的药理学抑制揭示了显著的血管表型，与对照相比，丝状伪足延伸的内皮尖端细胞的数量大大增加，尖端细胞标志物基因的表达增加。在dll（+/-）视网膜血管中的丝状伪足延伸需要血管生长因子VEGF，并且当VEGF信号传导被阻断时被抑制。尽管VEGF表达在dll 4（+/-）视网膜中没有显著改变，但与野生型相比，dll 4（+/-）血管显示VEGF受体2的表达增加，VEGF受体1的表达减少，表明它们可能对VEGF刺激更敏感。此外，当VEGF信号传导被阻断时，野生型TIP细胞中dll 4的表达本身降低，表明dll 4可能在VEGF下游作为VEGF介导的血管生成出芽的“制动器”。综上所述，这些数据揭示了Dll 4作为发育期间正常血管网络形成所需的血管发芽和血管分支的负调节剂。
Delta-like 4 (Dll4) is a transmembrane ligand for Notch receptors that is expressed in arterial blood vessels and sprouting endothelial cells. Here we show that Dll4 regulates vessel branching during development by inhibiting endothelial tip cell formation. Heterozygous deletion of dll4 or pharmacological inhibition of Notch signaling using gamma-secretase inhibitor revealed a striking vascular phenotype, with greatly increased numbers of filopodia-extending endothelial tip cells and increased expression of tip cell marker genes compared with controls. Filopodia extension in dll(+/-) retinal vessels required the vascular growth factor VEGF and was inhibited when VEGF signaling was blocked. Although VEGF expression was not significantly altered in dll4(+/-) retinas, dll4(+/-) vessels showed increased expression of VEGF receptor 2 and decreased expression of VEGF receptor 1 compared with wildtype, suggesting they could be more responsive to VEGF stimulation. in addition, expression of dll4 in wild-type tip cells was itself decreased when VEGF signaling was blocked, indicating that dll4 may act downstream of VEGF as a "brake" on VEGF-mediated angiogenic sprouting. Taken together, these data reveal Dll4 as a negative regulator of vascular sprouting and vessel branching that is required for normal vascular network formation during development.