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.
Highlights
Endothelial cell (EC) metabolism is thought to be one of the driving forces for angiogenesis
We screened a library of 619 highly purified metabolites encompassing a broad spectrum of chemical entities for their ability to affect growth of bovine choroidal microvascular EC (BCEC), in the presence or in the absence of VEGF
We focused our analysis on one of these, ManN, a hexosamine originally identified as a component of bacterial cell wall[15] because it showed the most potent and consistent effects
Summary
Endothelial cell (EC) metabolism is thought to be one of the driving forces for angiogenesis. 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. Aberrant glycosylation patterns have been documented during oncogenic transformation and progression of cancer and it has been proposed that inhibiting glycosylation may result in suppression of key angiogenesis pathways, including VEGF/VEGFR2 and Notch[10]. We hypothesized that testing the effects of metabolites on ECs may be a strategy to identify pro- and/or anti-angiogenic targets Such approach might result in better understanding of the role of metabolism in angiogenesis and potentially in resistance mechanism(s) toward anti-angiogenic and other therapies for cancer. We report that the hexosamine mannosamine (2Amino-2-deoxy-D-mannose or ManN hereafter) inhibits protein glycosylation and yet stimulates EC proliferation in vitro. We further examine its biological effects in other in vitro and in vivo models, as well as its possible mechanisms of action
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