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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:651.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Protein Modification by O-Linked GlcNAc Reduces Angiogenesis by Inhibiting Akt Activity in Endothelial Cells

Bai Luo; Yudi Soesanto; Donald A. McClain

From the Division of Endocrinology, University of Utah School of Medicine, Salt Lake City, Utah.

Correspondence to Dr Donald McClain, Division of Endocrinology, University of Utah, Salt Lake City, UT 84132. E-mail donald.mcclain{at}hsc.utah.edu

Objective— Glucose flux through the hexosamine biosynthesis pathway (HBP) has been implicated in the development of diabetic vascular complications. O-linked N-acetylglucosamine (O-GlcNAc) modification on protein is the major mechanism mediating the actions of the HBP. Impaired angiogenesis is well-recognized in diabetes; however, the mechanisms are not completely defined. Here, we investigated the role of protein O-GlcNAc modification in angiogenesis.

Methods and Results— In a mouse aortic ring assay, elevated O-GlcNAc levels induced by high-fat diet, streptozotocin-induced diabetes, or in vitro glucosamine treatment were associated with impaired angiogenesis. In cultured human umbilical vein endothelial cells and EA.hy926 endothelial cells, glucosamine increased protein O-GlcNAc modification and inhibited cell migration and capillary-like structure formation. Conversely, removal of O-GlcNAc by adenoviral-mediated overexpression of O-GlcNAcase improved these steps of angiogenesis. Also, high concentrations of glucose reduced capillary-like structure formation of human umbilical vein endothelial cells. Akt was recognized by an O-GlcNAc specific lectin, and glucosamine increased the amounts of Akt protein in these lectin precipitates. Increased glycosylation paralleled reduced Akt activity in endothelial cells.

Conclusion— These results suggest that elevated protein O-GlcNAc modification through the HBP impairs angiogenesis in endothelial cells, possibly by inhibiting Akt signaling.

Angiogenesis is impaired in diabetes. Here, we demonstrate that elevated O-GlcNAc levels inhibit vascular sprouting from mouse aortic rings and migration and capillary-like structure formation of endothelial cells. Akt signaling plays a key role in this O-GlcNAc–mediated angiogenesis regulation.

Key Words: hexosamine • angiogenesis • O-GlcNAc • endothelial cells • Akt

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