University of Science and Technology of China, No.96, Jinzhai Road Baohe District, Hefei, Anhui, 230026, PR China; Glycochemistry and Glycobiology Lab, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China; University of Chinese Academy of Sciences, No.19A, Yuquan Road, Beijing 100049, PR China.
Glycochemistry and Glycobiology Lab, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China; University of Chinese Academy of Sciences, No.19A, Yuquan Road, Beijing 100049, PR China; School of Pharmacy, Zunyi Medical University, 201 Dalian Road, Zunyi 563003, PR China.
Carbohydr Polym. 2019 Mar 1;207:502-509. doi: 10.1016/j.carbpol.2018.11.091. Epub 2018 Dec 6.
More and more evidences suggested that sulfated natural glycans had impact on angiogenesis. However, the molecular targets and functional mechanism of glycans are still vague. JCS1S2 was the sulfated mannoglucan featured with a backbone of 1, 4-linked β-Manp and 1, 4-linked α-Glcp with sulfation at C-6 of β-Manp and α-Glcp residues, respectively. The degree of substitution of this sulfated polysaccharide was 1.74 and its molecular weight was 56.2 kDa. We provided evidences that JCS1S2 could disrupt angiogenesis both in vitro and in vivo. This sulfated polysaccharide inhibited migration and tube formation of human microvascular endothelial cells (HMEC-1) whereas showed no effect on the cells proliferation. Further study uncovered that JCS1S2 bound to both VEGF (vascular endothelial growth factor) (K value: 4.82 × 10) and VEGFR2 (Vascular Endothelial Growth Factor Receptor 2) (K value: 1.50 × 10) to inactivate VEGFR2 phosphorylation. In addition, JCS1S2 blocked downstream signaling and impaired the expression of VEGF and its transcription factor AP-1 (Activator protein-1). These results demonstrated that JCS1S2 interrupted angiogenesis via blocking VEGF signaling transduction and could be a potential anti-angiogenetic agent for disease treatment.
越来越多的证据表明，硫酸化天然糖胺聚糖对血管生成有影响。然而，糖胺聚糖的分子靶点和功能机制仍然不清楚。JCS1S2 是一种硫酸化甘露聚糖，其主链由 1,4-连接的 β-Manp 和 1,4-连接的 α-Glcp 组成，β-Manp 和 α-Glcp 残基上的 C-6 分别发生硫酸化。该硫酸化多糖的取代度为 1.74，分子量为 56.2 kDa。我们提供的证据表明，JCS1S2 可以在体外和体内破坏血管生成。这种硫酸化多糖抑制人微血管内皮细胞（HMEC-1）的迁移和管形成，但对细胞增殖没有影响。进一步的研究表明，JCS1S2 与 VEGF（血管内皮生长因子）（K 值：4.82×10）和 VEGFR2（血管内皮生长因子受体 2）（K 值：1.50×10）结合，使 VEGFR2 磷酸化失活。此外，JCS1S2 阻断下游信号通路，损害 VEGF 及其转录因子 AP-1（激活蛋白-1）的表达。这些结果表明，JCS1S2 通过阻断 VEGF 信号转导来干扰血管生成，可能是一种用于疾病治疗的潜在抗血管生成剂。
