Bischoff Lindsay J, Schrenk Sandra, Soroko Kara, Boscolo Elisa
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
bioRxiv. 2025 Jul 30:2025.07.24.666614. doi: 10.1101/2025.07.24.666614.
Sporadic venous malformation (VM) is associated with the hyperactivating p.L914F mutation in TIE2, a receptor tyrosine kinase essential for vascular development. This mutation is not found in hereditary VM, suggesting incompatibility with life when expressed during early vascular development. Therefore, we utilized a novel genetic mouse model that expresses TIE2 p.L914F to determine the phenotypical effects of this mutation during development.
( ) mice were generated and then validated for the presence of the transgene. The constitutive endothelial-specific line was used to activate expression of the mutant gene during early embryonic development. embryos experienced lethality at approximately embryonic day (E)9.5. 3-dimensional imaging of embryos and yolk sacs revealed impaired vascular remodeling in mutant animals, resulting in malformed vasculature with disorganized, dilated, and non-functional blood vessels. The abnormal vascular phenotype was not associated with total loss of erythroid cells or increased cell proliferation.
The mice used in this study represent a novel genetic model of TIE2 p.L914F-driven vascular disease. This study provides the first experimental evidence that this mutation is incompatible with early prenatal development due to its deleterious effects on the vasculature, illustrating the vital role of TIE2 signaling during vessel development and remodeling.
散发性静脉畸形（VM）与TIE2基因中的p.L914F激活突变相关，TIE2是一种对血管发育至关重要的受体酪氨酸激酶。遗传性VM中未发现这种突变，这表明在早期血管发育过程中表达该突变与生命不相容。因此，我们利用一种表达TIE2 p.L914F的新型基因小鼠模型来确定该突变在发育过程中的表型效应。
（ ）小鼠被培育出来，然后对转基因的存在进行了验证。使用组成型内皮特异性系在胚胎早期发育期间激活突变基因的表达。（ ）胚胎在大约胚胎第9.5天出现致死性。对胚胎和卵黄囊的三维成像显示突变动物的血管重塑受损，导致血管畸形，血管紊乱、扩张且无功能。异常的血管表型与红细胞的完全丧失或细胞增殖增加无关。
本研究中使用的（ ）小鼠代表了一种由TIE2 p.L914F驱动的血管疾病的新型遗传模型。这项研究提供了第一个实验证据，即由于该突变对脉管系统的有害影响，它与产前早期发育不相容，说明了TIE2信号在血管发育和重塑过程中的重要作用。
