Overexpression of delta-like 4 induces arterialization and attenuates vessel formation in developing mouse embryos
Overexpression of delta-like 4 induces arterialization and attenuates vessel formation in developing mouse embryos
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DOI：
10.1182/blood-2007-09-112748
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发表时间：
2008-09-01
期刊：
影响因子：
20.3
通讯作者：
Duarte, Antonio
中科院分区：
文献类型：
--
作者：
Trindade, Alexandre;Kumar, S. Ram;Duarte, Antonio
Notch信号通路在调节血管发育和血管生成中的重要性通过Notch受体和配体在血管内皮细胞（EC）中的表达以及在Notch受体或配体的突变体（特别是Dll 4）中观察到的血管表型来暗示。DLL 4在发育期间特异性表达于动脉EC中，并且单倍不足在小鼠中是胚胎致死的。为了解决Dll 4在血管发育中的作用，我们产生了mDll 4条件性过表达的转基因小鼠，其与组成型重组酶cre系杂交。双转基因胚胎表现出明显增大的背侧嵴（DA），并在胚胎第10.5天（E10.5）前死亡，表现出不同程度的过早动静脉融合。静脉显示动脉标记物的异位表达。其他缺陷包括减少血管发芽，EC增殖和迁移。mDll 4过表达还抑制VEGF信号传导并增加血管周围的纤连蛋白积聚。在EC中DLL 4-FL（Dll 4-全长）的体外和体内研究概括了许多mDll 4转基因发现，包括减少的管形成、减少的血管分支、更少的血管、增加的周细胞募集和增加的纤连蛋白表达。这些结果确立了Dll 4在动脉身份确定以及受剂量和位置影响的血管生成调节中的作用。
The importance of Notch signaling pathway in the regulation of vascular development and angiogenesis is suggested by the expression of Notch receptors and ligands in vascular endothelial cells (ECs) and the observed vascular phenotypes in mutants of Notch receptors or ligands, especially Dll4. DLL4 is specifically expressed in arterial ECs during development, and haplo-insufficiency is embryonically lethal in mice. To address the role of Dll4 in vascular development, we produced mDll4 conditionally overexpressed transgenic mice that were crossed with constitutive recombinase cre lines. Double transgenic embryos displayed grossly enlarged dorsal aortae (DA) and died before embryonic day 10.5 (E10.5), showing a variable degree of premature arteriovenous fusion. Veins displayed ectopic expression of arterial markers. Other defects included reduced vascular sprouting, EC proliferation, and migration. mDll4 overexpression also inhibited VEGF signaling and increased fibronectin accumulation around the vessels. In vitro and in vivo studies of DLL4-FL (Dll4-full-length) in ECs recapitulate many of the mDll4 transgenics findings, including decreased tube formation, reduced vascular branching, fewer vessels, increased pericyte recruitment, and increased fibronectin expression. These results establish the role of Dll4 in arterial identity determination, and regulation of angiogenesis subject to dose and location.