foxc1a and foxc1b differentially regulate angiogenesis from arteries and veins by modulating Vascular Endothelial Growth Factor signalling
foxc1a and foxc1b differentially regulate angiogenesis from arteries and veins by modulating Vascular Endothelial Growth Factor signalling
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DOI：
10.1101/417931
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发表时间：
2018-09
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影响因子：
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通讯作者：
Z. Jiang;Teri Evans;A. M. Savage;M. Loose;T. Chico;F. V. van Eeden;R. Wilkinson
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文献类型：
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作者：
Z. Jiang;Teri Evans;A. M. Savage;M. Loose;T. Chico;F. V. van Eeden;R. Wilkinson
叉头转录因子Foxc1和Foxc2对于在哺乳动物中建立完整的血管网络至关重要。这些基因如何与内皮信号通路相互作用以发挥其功能仍不完全清楚。我们在斑马鱼中产生了新的foxc1a和foxc1b突变体，它们是哺乳动物Foxc1的斑马鱼同源物，以确定它们在血管生成过程中的功能。foxc1a突变体表现为颅静脉的异常形成，包括原始后脑通道（PHBC），血管内皮生长因子（VEGF）受体在这些通道中的表达降低，以及中心动脉的缺失。Foxc1b突变体是正常的，而foxc1a；Foxc1b双突变体表现为躯干节段性动脉的异位血管生成。Dll4/Notch信号在foxc1a中减少；foxc1b双突变动脉和异位血管生成可以通过诱导Notch或抑制Vegfc信号传导来抑制。我们得出结论，foxc1a和foxc1b通过诱导VEGF受体表达促进静脉发芽，同时通过诱导Dll4/Notch信号传导抑制动脉发芽，从而在协调血管生成中发挥代偿性和情境依赖性作用。foxc1a/b介导的VEGF-Dll4/Notch负反馈的促血管生成轴和抗血管生成轴的诱导使竞争在发育中的血管床内平衡动脉和静脉血管生成。在斑马鱼胚胎中，foxc1a和foxc1b通过促进促血管生成的血管内皮生长因子信号和抗血管生成的Dll4/Notch信号的竞争，促进静脉血管生成，抑制动脉血管生成。
The forkhead transcription factors Foxc1 and Foxc2 are essential to establish intact vascular networks in mammals. How these genes interact with endothelial signalling pathways to exert their functions remains incompletely understood. We have generated novel zebrafish mutants in foxc1a and foxc1b, the zebrafish orthologues of mammalian Foxc1, to determine their function during angiogenesis. foxc1a mutants display abnormal formation of cranial veins including the primordial hindbrain channels (PHBC), reduced Vascular Endothelial Growth Factor (VEGF) receptor expression in these and loss of central arteries. foxc1b mutants are normal, whereas foxc1a; foxc1b double mutants exhibit ectopic angiogenesis from trunk segmental arteries. Dll4/Notch signalling is reduced in foxc1a; foxc1b double mutant arteries and ectopic angiogenesis can be suppressed by induction of Notch or inhibition of Vegfc signalling. We conclude that foxc1a and foxc1b play compensatory and context-dependent roles to co-ordinate angiogenesis by promoting venous sprouting via induction of VEGF receptor expression whilst antagonising arterial sprouting by inducing Dll4/Notch signalling. foxc1a/b mediated induction of both pro- and anti-angiogenic axes of VEGF-Dll4/Notch negative feedback imparts competition to balance arterial and venous angiogenesis within developing vascular beds. Summary Statement foxc1a and foxc1b promote angiogenesis from veins and suppress angiogenesis from arteries by promoting competing pro-angiogenic Vascular Endothelial Growth Factor signalling, and anti-angiogenic Dll4/Notch signalling in zebrafish embryos.