Angiogenesis LAB, Institute of Genetics and Biophysics "Adriano Buzzati-Traverso"-CNR, Naples 80131, Italy.
Angiogenesis LAB, Institute of Genetics and Biophysics "Adriano Buzzati-Traverso"-CNR, Naples 80131, Italy.
Cell Rep. 2018 Jun 19;23(12):3635-3646. doi: 10.1016/j.celrep.2018.05.067.
Placental growth factor (PlGF) is a proangiogenic member of the vascular endothelial growth factor (VEGF) family playing a central role in pathological angiogenesis. PlGF-DE is a PlGF variant unable to bind vascular endothelial growth factor receptor 1 (VEGFR-1) but still able to generate heterodimer with VEGF-A. We have generated PlGF-DE knockin mice that are vital and fertile and show unaltered expression of Plgf, Vegf-a, Vegfr-1, and Vegfr-2 compared with wild-type mice. Interestingly, these mutants showed additional and remarkable angiogenesis impairment in tumor growth, hindlimb ischemia, and choroidal neovascularization compared with both PlGF knockout and wild-type mice. These findings provided insights on VEGF-A/PlGF heterodimer function, which was able to rescue neovascularization and vascular leakage in PlGF-DE knockin mice. Collectively, these data show that PlGF-DE knockin mouse could be considered the full functional knockout of PlGF, suggesting a reassessment of the phenotypes of knockout mice for the genes whose products are able to generate heterodimeric proteins.
胎盘生长因子（PlGF）是血管内皮生长因子（VEGF）家族的一种促血管生成成员，在病理性血管生成中起核心作用。PlGF-DE 是一种无法与血管内皮生长因子受体 1（VEGFR-1）结合的 PlGF 变体，但仍能与 VEGF-A 生成异二聚体。我们已经生成了 PlGF-DE 敲入小鼠，它们具有生命力和生育能力，与野生型小鼠相比，Plgf、Vegf-a、Vegfr-1 和 Vegfr-2 的表达没有改变。有趣的是，与 PlGF 敲除和野生型小鼠相比，这些突变体在肿瘤生长、后肢缺血和脉络膜新生血管化方面表现出额外的、显著的血管生成损伤。这些发现为 VEGF-A/PlGF 异二聚体功能提供了新的认识，该功能能够挽救 PlGF-DE 敲入小鼠的新生血管形成和血管渗漏。总之，这些数据表明 PlGF-DE 敲入小鼠可以被认为是 PlGF 的完全功能敲除，这表明需要重新评估那些其产物能够生成异二聚体蛋白的基因的敲除小鼠的表型。
