Advanced glycation end products induce immature angiogenesis in in vivo and ex vivo mouse models
Advanced glycation end products induce immature angiogenesis in in vivo and ex vivo mouse models
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高级糖基化终产物在体内和离体小鼠模型中诱导不成熟的血管生成
DOI：
10.1152/ajpheart.00473.2019
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发表时间：
2020-03-01
影响因子：
4.8
通讯作者：
Huang, Qiaobing
中科院分区：
文献类型：
--
作者：
Chen, Lixian;Cui, Yun;Huang, Qiaobing
增殖性糖尿病视网膜病变（PDR）是一种主要涉及病理性血管生成的进行性疾病，其特征是不成熟、脆弱且容易出血的新血管的发育。晚期糖基化终末产物 (AGE) 和 AGE 受体 (RAGE) 在糖尿病视网膜病变的进展中发挥重要作用。我们之前的研究表明，AGEs 通过 RhoA/Rho 相关蛋白激酶 (ROCK) 途径诱导 moesin 磷酸化，从而促进 HUVEC 血管生成。本研究的目的是进一步证实AGE诱导的体内血管生成以及RAGE的参与。 ROCK和moesin在此过程中被磷酸化。我们在 AGE 处理的小鼠模型中进行了这项研究，并在多个体内和离体模型中进行了各种血管生成测定。结果表明，AGEs 促进成年和出生后小鼠的整体视网膜和小鼠主动脉环以及基质胶塞中显着的新生血管形成，这始终伴随着莫斯蛋白磷酸化的增加。在小鼠中，RAGE 敲除或 ROCK 抑制剂 Y27632 给药均可减弱 AGE 诱发的新血管形成和 moesin 磷酸化的增加。我们还通过证明微血管中周细胞覆盖率的降低和内皮排列紊乱，揭示了 AGE 促进的血管生成的病理特征。总之，这项研究提供了体内证据，表明 AGE 通过与 RAGE 结合、激活 RhoA/ROCK 信号通路并诱导 moesin 磷酸化来诱导未成熟血管生成。新的和值得注意的高级糖基化终末产物 (AGE) 诱导新生血管的形成以及视网膜和主动脉环中 moesin 的磷酸化需要 AGE 受体。 AGE 通过 RhoA/ROCK 途径增加视网膜和主动脉环中的新生血管和 moesin 的磷酸化。 AGE 处理的小鼠视网膜和主动脉环中 AGE 诱导的未成熟血管生成。 AGE-RAGE 轴和 moesin 可能是克服相关疾病的候选靶点。
Proliferative diabetic retinopathy (PDR) is a progressive disease predominantly involving pathological angiogenesis and is characterized by the development of immature, fragile, and easily hemorrhagic new vessels. Advanced glycation end products (AGEs) and the receptor for AGEs (RAGE) play important roles in the progression of diabetic retinopathy. Our previous studies demonstrated that AGEs promoted HUVEC angiogenesis by inducing moesin phosphorylation via RhoA/Rho-associated protein kinase (ROCK) pathway. The aim of this study was to further confirm AGE-induced angiogenesis in vivo and the involvement of RAGE. ROCK, and moesin phosphorylation in this process. We performed the study in an AGE-treated mouse model with various angiogenesis assays in multiple in vivo and ex vivo models. The results demonstrated that AGEs promoted significant neovascularization in whole mount retina and mouse aortic ring of adult and postnatal mice and in Matrigel plug as well, which were consistently accompanied by increased moesin phosphorylation. The increase of AGE-evoked neovascularization and moesin phosphorylation were both attenuated by RAGE knockout or ROCK inhibitor Y27632 administration in mice. We also revealed the pathological characteristics of AGE-promoted angiogenesis by demonstrating the decrease of pericyte coverage and the disarranged endothelial alignment in microvessels. In conclusion, this study provides in vivo evidences that AGEs induce immature angiogenesis by binding to RAGE, activating the RhoA/ROCK signal pathway and inducing moesin phosphorylation.NEW & NOTEWORTHY Advanced glycation end product (AGE)-induced formation of neovessels and phosphorylation of moesin in retina and aortic ring required AGE receptors. AGEs increased neovessels and the phosphorylation of moesin in retina and aortic ring via RhoA/ROCK pathway. AGE-induced immature angiogenesis in AGE-treated mouse retina and aortic ring. The AGE-RAGE axis and moesin could be candidate targets for overcoming relative diseases.