Department of Korean Medical Science, School of Korean Medicine and Healthy Aging Korean Medical Research Center, Pusan National University, Yangsan, Gyeongnam, 50612, Korea.
Department of Molecular Biology, College of Natural Sciences, Pusan National University, Geumjeong-gu, Busan, 46241, Korea.
Exp Mol Med. 2019 Oct 11;51(10):1-13. doi: 10.1038/s12276-019-0311-6.
Angiogenesis should be precisely regulated because disordered neovascularization is involved in the aggravation of multiple diseases. The vascular endothelial growth factor (VEGF)-A/VEGF receptor 2 (VEGFR-2) axis is crucial for controlling angiogenic responses in vascular endothelial cells (ECs). Therefore, inactivating VEGFR-2 signaling may effectively suppress aberrant angiogenesis and alleviate related symptoms. In this study, we performed virtual screening, identified the synthetic disaccharide 6'-sialylgalactose (6SG) as a potent VEGFR-2-binding compound and verified its high binding affinity by Biacore assay. 6SG effectively suppressed VEGF-A-induced VEGFR-2 phosphorylation and subsequent in vitro angiogenesis in HUVECs without inducing cytotoxicity. 6SG also inhibited VEGF-A-induced extracellular-regulated kinase (ERK)/Akt activation and actin stress fiber formation in HUVECs. We demonstrated that 6SG inhibited retinal angiogenesis in a mouse model of retinopathy of prematurity and tumor angiogenesis in a xenograft mouse model. Our results suggest a potential therapeutic benefit of 6SG in inhibiting angiogenesis in proangiogenic diseases, such as retinopathy and cancer.
血管生成应精确调控，因为血管新生异常与多种疾病的恶化有关。血管内皮生长因子（VEGF）-A/VEGF 受体 2（VEGFR-2）轴对于控制血管内皮细胞（EC）的血管生成反应至关重要。因此，抑制 VEGFR-2 信号通路可能有效抑制异常血管生成并缓解相关症状。在这项研究中，我们进行了虚拟筛选，鉴定出合成二糖 6'-唾液酸半乳糖（6SG）是一种有效的 VEGFR-2 结合化合物，并通过 Biacore 实验验证了其高结合亲和力。6SG 有效抑制了 VEGF-A 诱导的 VEGFR-2 磷酸化及随后在 HUVECs 中的体外血管生成，同时不诱导细胞毒性。6SG 还抑制了 VEGF-A 诱导的 HUVECs 中细胞外调节激酶（ERK）/Akt 的激活和肌动蛋白应力纤维形成。我们证明，6SG 抑制了早产儿视网膜病变模型中的视网膜血管生成和异种移植小鼠模型中的肿瘤血管生成。我们的结果表明，6SG 在抑制血管生成性疾病（如视网膜病变和癌症）方面具有潜在的治疗益处。
