Increased dicarbonyl metabolism in endothelial cells in hyperglycemia induces anoikis and impairs angiogenesis by RGD and GFOGER motif modification.
Chronic vascular disease in diabetes is associated with disruption of extracellular matrix (ECM) interactions with adherent endothelial cells, compromising cell survival and impairing vasculature structure. Loss of functional contact with integrins activates anoikis and impairs angiogenesis. The metabolic dysfunction underlying this vascular damage and disruption is unclear. Here, we show that increased modification of vascular basement membrane type IV collagen by methylglyoxal, a dicarbonyl glycating agent with increased formation in hyperglycemia, formed arginine-derived hydroimidazolone residues at hotspot modification sites in RGD and GFOGER integrin-binding sites of collagen, causing endothelial cell detachment, anoikis, and inhibition of angiogenesis. Endothelial cells incubated in model hyperglycemia in vitro and experimental diabetes in vivo produced the same modifications of vascular collagen, inducing similar responses. Pharmacological scavenging of methylglyoxal prevented anoikis and maintained angiogenesis, and inhibition of methylglyoxal metabolism with a cell permeable glyoxalase I inhibitor provoked these responses in normoglycemia. Thus, increased formation of methylglyoxal and ECM glycation in hyperglycemia impairs endothelial cell survival and angiogenesis and likely contributes to similar vascular dysfunction in diabetes.
Dobler
Darin
D
Department of Biological Sciences, University of Essex, Colchester, Essex CO4 3SQ, UK.
Ahmed
Naila
N
Song
Lijiang
L
Eboigbodin
Kevin E
KE
Thornalley
Paul J
PJ
D000595:Amino Acid Sequence; D023102:Anoikis / Q000502:physiology*; D002448:Cell Adhesion; D002460:Cell Line; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D005109:Extracellular Matrix / Q000502:physiology; D006031:Glycosylation; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D013058:Mass Spectrometry; D008958:Models, Molecular; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D009842:Oligopeptides / Q000378:metabolism*; D010449:Peptide Mapping
D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid