Inhibition of protein glycosylation is a novel pro-angiogenic strategy that acts via activation of stress pathways

Cuiling Zhong, Pin Li, Sulabha Argade, Lixian Liu, Anastasia Chilla’, Wei Liang, Hong Xin, Brian Eliceiri, Biswa Choudhury and Napoleone Ferrara ()
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Cuiling Zhong: University of California, San Diego
Pin Li: University of California, San Diego
Sulabha Argade: University of California, San Diego
Lixian Liu: University of California, San Diego
Anastasia Chilla’: University of California, San Diego
Wei Liang: University of California, San Diego
Hong Xin: University of California, San Diego
Brian Eliceiri: University of California, San Diego
Biswa Choudhury: University of California, San Diego
Napoleone Ferrara: University of California, San Diego

Nature Communications, 2020, vol. 11, issue 1, 1-21

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-20108-0

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