Glycation of fibronectin inhibits VEGF-induced angiogenesis by uncoupling VEGF receptor-2-c-Src crosstalk
Glycation of fibronectin inhibits VEGF-induced angiogenesis by uncoupling VEGF receptor-2-c-Src crosstalk
复制标题
纤连蛋白的糖化通过解偶联 VEGF 受体 — 2 — c — Src 串扰抑制 VEGF — 诱导的血管生成
DOI：
10.1111/jcmm.15552
复制
发表时间：
2020-07-01
影响因子：
5.3
通讯作者：
Wang, Liqun
中科院分区：
文献类型：
--
作者：
Chen, Tangting;Dong, Jinling;Wang, Liqun
细胞外基质蛋白的糖基化已被证明有助于血管并发症的发病机制。然而，没有以前的报告表明糖化纤维连接蛋白（FN）在血管内皮生长因子（VEGF）诱导的血管生成的作用。因此，本研究旨在研究糖化FN对VEGF信号传导的影响，并阐明所涉及的分子机制。将FN与丙酮醛（MGO）体外孵育以合成糖化FN，并将人脐静脉内皮细胞（HUVECs）接种于未修饰和MGO糖化的FN上。然后，测量VEGF诱导的血管生成和VEGF诱导的VEGF受体-2（VEGFR-2）信号传导激活。结果表明，MG O-糖基化FN中正常FN阳性条带（260 kD）消失，晚期糖基化终产物（AGEs）出现，糖基化FN明显向高分子量转变。FN的糖基化可抑制VEGF诱导的VEGF受体-2（VEGFR-2）、Akt和ERK 1/2的活化以及VEGF诱导的细胞迁移、增殖和管形成。FN的糖基化还通过AGEs受体（AGEs）螯合c-Src来抑制c-Src向VEGFR-2的募集，并且抗-AGEs抗体恢复VEGF诱导的VEGFR-2、Akt和ERK 1/2磷酸化、内皮细胞迁移、增殖和管形成。此外，FN的糖基化显着抑制VEGF诱导的小鼠皮下组织中植入Matrigel塞的新生血管形成。综上所述，这些数据表明，FN的糖基化可以通过解偶联VEGFR-2-c-Src相互作用来抑制VEGF信号传导和VEGF诱导的血管生成。这可能为糖尿病缺血性疾病血管生成受损提供了一种新的机制。
Glycation of extracellular matrix proteins has been demonstrated to contribute to the pathogenesis of vascular complications. However, no previous report has shown the role of glycated fibronectin (FN) in vascular endothelial growth factor (VEGF)-induced angiogenesis. Thus, this study aimed to investigate the effects of glycated FN on VEGF signalling and to clarify the molecular mechanisms involved. FN was incubated with methylglyoxal (MGO) in vitro to synthesize glycated FN, and human umbilical vein endothelial cells (HUVECs) were seeded onto unmodified and MGO-glycated FN. Then, VEGF-induced angiogenesis and VEGF-induced VEGF receptor-2 (VEGFR-2) signalling activation were measured. The results demonstrated that normal FN-positive bands (260 kD) vanished and advanced glycation end products (AGEs) appeared in MGO-glycated FN and glycated FN clearly changed to a higher molecular mass. The glycation of FN inhibited VEGF-induced VEGF receptor-2 (VEGFR-2), Akt and ERK1/2 activation and VEGF-induced cell migration, proliferation and tube formation. The glycation of FN also inhibited the recruitment of c-Src to VEGFR-2 by sequestering c-Src through receptor for AGEs (RAGE) and the anti-RAGE antibody restored VEGF-induced VEGFR-2, Akt and ERK1/2 phosphorylation, endothelial cell migration, proliferation and tube formation. Furthermore, the glycation of FN significantly inhibited VEGF-induced neovascularization in the Matrigel plugs implanted into subcutaneous tissue of mice. Taken together, these data suggest that the glycation of FN may inhibit VEGF signalling and VEGF-induced angiogenesis by uncoupling VEGFR-2-c-Src interaction. This may provide a novel mechanism for the impaired angiogenesis in diabetic ischaemic diseases.