Inhibition of protein glycosylation is a novel pro-angiogenic strategy that acts via activation of stress pathways.
Inhibition of protein glycosylation is a novel pro-angiogenic strategy that acts via activation of stress pathways.
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抑制蛋白质糖基化是一种新的促血管生成策略，它通过激活应激途径发挥作用。
DOI：
10.1038/s41467-020-20108-0
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发表时间：
2020-12-10
影响因子：
16.6
通讯作者：
Ferrara N
中科院分区：
文献类型：
--
作者：
Zhong C;Li P;Argade S;Liu L;Chilla' A;Liang W;Xin H;Eliceiri B;Choudhury B;Ferrara N
血管内皮细胞(EC)代谢被认为是血管生成的驱动力之一。本文报道了氨基己糖胺D-甘露糖胺(MANN)是牛和人微血管内皮细胞的有丝分裂原和生存因子，并与血管内皮生长因子(VEGF)相加。甘露糖抑制内皮细胞的糖基化，并诱导N-糖链和O-糖链的显著变化。我们进一步证明，Mann和两种N-糖基化抑制剂通过激活JNK和内质网应激引起的未折叠蛋白反应来刺激EC的增殖。在小鼠皮肤损伤模型中，MANN导致血管生成增强。与对照组相比，曼恩还促进了小鼠后肢缺血模型的血管生成，加速了肢体血流的恢复。此外，眼内注射曼宁可诱导视网膜新生血管形成。因此，抑制蛋白糖基化后激活应激通路可以促进内皮细胞的增殖和血管生成，可能是治疗缺血性疾病的一种策略。治疗性血管生成具有诱导和维持新血管的潜力，从而改善缺血性疾病患者的预后。甘露三胺通过激活应激途径发挥内皮细胞有丝分裂原/生存因子的作用，在多种疾病中可能有助于保护和再生血管内皮细胞。
Endothelial cell (EC) metabolism is thought to be one of the driving forces for angiogenesis. Here we report the identification of the hexosamine D-mannosamine (ManN) as an EC mitogen and survival factor for bovine and human microvascular EC, with an additivity with VEGF. ManN inhibits glycosylation in ECs and induces significant changes in N-glycan and O-glycan profiles. We further demonstrate that ManN and two N-glycosylation inhibitors stimulate EC proliferation via both JNK activation and the unfolded protein response caused by ER stress. ManN results in enhanced angiogenesis in a mouse skin injury model. ManN also promotes angiogenesis in a mouse hindlimb ischemia model, with accelerated limb blood flow recovery compared to controls. In addition, intraocular injection of ManN induces retinal neovascularization. Therefore, activation of stress pathways following inhibition of protein glycosylation can promote EC proliferation and angiogenesis and may represent a therapeutic strategy for treatment of ischemic disorders. Therapeutic angiogenesis has the potential of inducing and maintaining new blood vessels and thus improving outcomes in patients with ischemic disorders. Mannosamine functions as an endothelial cell mitogen/survival factor through activation of stress pathways and might be useful to protect and regenerate the vascular endothelium in a variety of disorders.
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影响因子：
--
作者：
Chen YJ;Yao CC;Huang CH;Chang HH;Young TH
通讯作者：
Young TH
影响因子：
4.3
作者：
Griesemer M;Young C;Robinson AS;Petzold L
通讯作者：
Petzold L
影响因子：
6.2
作者：
Alonso-Sande, Maria;des Rieux, Anne;Alonso, Maria J.
通讯作者：
Alonso, Maria J.
影响因子：
--
作者：
FERRARA, N;FUJII, DK;WEINER, RI
通讯作者：
WEINER, RI
影响因子：
4.2
作者：
Farley, JR;Magnusson, P
通讯作者：
Magnusson, P