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

Nature communications (2020-12-12)
Cuiling Zhong, Pin Li, Sulabha Argade, Lixian Liu, Anastasia Chilla', Wei Liang, Hong Xin, Brian Eliceiri, Biswa Choudhury, Napoleone Ferrara
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Tunicamycin from Streptomyces sp.
Sigma-Aldrich
D-Mannosamine hydrochloride
Sigma-Aldrich
Adenosine 3′,5′-cyclic monophosphate tris salt, ≥97% (HPLC), powder
Sigma-Aldrich
4-Nitrophenyl α-D-glucopyranoside, ≥99%
Sigma-Aldrich
Dimethyl sulfoxide, Hybri-Max, sterile-filtered, BioReagent, suitable for hybridoma, ≥99.7%
Sigma-Aldrich
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Sigma-Aldrich
SP600125, ≥98% (HPLC)
USP
Glucosamine hydrochloride, United States Pharmacopeia (USP) Reference Standard
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MISSION® esiRNA, targeting human MAPK9
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α-Glucosidase from Saccharomyces cerevisiae, Type I, lyophilized powder, ≥10 units/mg protein (using p-nitrophenyl α-D-glucoside as substrate.)
Sigma-Aldrich
α-Mannosidase from Canavalia ensiformis (Jack bean), ammonium sulfate suspension, ≥15 units/mg protein (biuret)
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β-Glucosidase from almonds, lyophilized powder, ≥2 units/mg solid
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Keratinocyte Growth Factor human, KGF, recombinant, expressed in E. coli, powder, suitable for cell culture
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4-Phenylbutyric acid, 99%
Sigma-Aldrich
(1S,6S,7R,8R,8aR)-1,6,7,8-Tetrahydroxyindolizidine, 98%
USP
Mannose, United States Pharmacopeia (USP) Reference Standard