Institute of Physiology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
Physiology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
Acta Physiol (Oxf). 2021 Feb;231(2):e13556. doi: 10.1111/apha.13556. Epub 2020 Sep 15.
In the pathogenesis of several diseases, neo-angiogenesis is increased (e.g. tumour growth). The peptide L-glutamyl-L-tryptophan (EW/IM862) has been claimed to exhibit inhibitory effects on tumour growth in vivo. However, the potential role of natural peptides with respect to anti-angiogenic properties is unsettled. The current study explores anti-angiogenic effects of the dipeptides WL, EW, IW and WE.
Using a bottom-up strategy, we first evaluated the effects of the peptides on VEGFR-2 signalling and quantified their effects in different angiogenesis assays. WL consistently had the strongest effects on phosphorylation of VEGFR-2 and downstream signalling. Therefore, this peptide was chosen in comparison with EW to further assess anti-angiogenic properties. However, sprout formation in three-dimensional (3D) fibrin gel bead assay was significantly inhibited by EW only. Furthermore, vessel sprouting in the mouse aortic ring assay was decreased by the presence of WL and EW compared to control. Results from a chorioallantoic membrane assay showed that under vascular endothelial growth factor (VEGF) stimulation WL and EW decreased the number of blood vessels versus control. These results were in line with those obtained in a matrigel plug assay. The VEGF-induced increase in the haemoglobin content was nearly abolished when treatment was combined with either WL or EW application. In the murine model of oxygen-induced retinopathy, WL exhibited a small albeit significant anti-angiogenic effect.
Comprehensive screening of WL suggests an anti-angiogenic effect, demonstrated in in vitro, ex vivo and in vivo models. Thus, WL is a dipeptide with potential anti-angiogenic effects and is worthy for further exploration.
在几种疾病的发病机制中，新生血管形成增加（例如肿瘤生长）。据称，肽 L-谷氨酰-L-色氨酸（EW/IM862）具有体内抑制肿瘤生长的作用。然而，天然肽具有抗血管生成特性的潜在作用尚未确定。本研究探讨了二肽 WL、EW、IW 和 WE 的抗血管生成作用。
采用自下而上的策略，我们首先评估了这些肽对 VEGFR-2 信号的影响，并在不同的血管生成测定中量化了它们的作用。WL 对 VEGFR-2 磷酸化和下游信号的影响始终最强。因此，与 EW 相比，选择该肽进一步评估其抗血管生成特性。然而，只有 EW 显著抑制了三维（3D）纤维蛋白凝胶珠测定中的芽形成。此外，与对照相比，WL 和 EW 降低了小鼠主动脉环测定中的血管芽形成。鸡胚绒毛尿囊膜测定结果表明，与对照相比，WL 和 EW 降低了血管内皮生长因子（VEGF）刺激下的血管数量。这些结果与在 Matrigel plugs 测定中获得的结果一致。当用 WL 或 EW 联合治疗时，VEGF 诱导的血红蛋白含量增加几乎被消除。在氧诱导的视网膜病变小鼠模型中，WL 表现出微小但显著的抗血管生成作用。
对 WL 的综合筛选表明其具有抗血管生成作用，在体外、离体和体内模型中均得到证实。因此，WL 是一种具有潜在抗血管生成作用的二肽，值得进一步探索。
