Role of endothelial N-glycan mannose residues in monocyte recruitment during atherogenesis.
OBJECTIVE
Upregulated expression of endothelial adhesion molecules and subsequent binding to cognate monocytic receptors are established paradigms in atherosclerosis. However, these proteins are the scaffolds, with their posttranslational modification with sugars providing the actual ligands. We recently showed that tumor necrosis factor-α increased hypoglycosylated (mannose-rich) N-glycans on the endothelial surface. In the present study, our aim was to determine whether (1) hypoglycosylated N-glycans are upregulated by proatherogenic stimuli (oscillatory flow) in vitro and in vivo, and (2) mannose residues on hypoglycosylated endothelial N-glycans mediate monocyte rolling and adhesion.


RESULTS
Staining with the mannose-specific lectins concanavalin A and lens culinaris agglutinin was increased in human aortic endothelial cells exposed to oscillatory shear or tumor necrosis factor-α and at sites of plaque development and progression in both mice and human vessels. Increasing surface N-linked mannose by inhibiting N-glycan processing potentiated monocyte adhesion under flow during tumor necrosis factor-α stimulation. Conversely, enzymatic removal of high-mannose N-glycans, or masking mannose residues with lectins, significantly decreased monocyte adhesion under flow. These effects occurred without altering induced expression of adhesion molecule proteins.


CONCLUSIONS
Hypoglycosylated (high mannose) N-glycans are present on the endothelial cell surface at sites of early human lesion development and are novel effectors of monocyte adhesion during atherogenesis.
Department of Pathology, University of Alabama at Birmingham, 901 19th St S, BMRII 532, Birmingham, AL 35294, USA.
David W
DW
Scott
Jie
J
Chen
Balu K
BK
Chacko
James G
JG
Traylor
Anthony W
AW
Orr
Rakesh P
RP
Patel
D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D002450:Cell Communication; D002465:Cell Movement; D042783:Endothelial Cells / Q000502:physiology*; D006031:Glycosylation; D006801:Humans; D008358:Mannose / Q000502:physiology*; D009000:Monocytes / Q000502:physiology*; D011134:Polysaccharides / Q000737:chemistry*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology; D043323:alpha-Mannosidase / Q000037:antagonists & inhibitors
D011134:Polysaccharides; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D043323:alpha-Mannosidase; D008358:Mannose