Abstract 704: Glycation of Vitronectin Inhibits VEGF-induced Angiogenesis by Uncoupling VEGF Receptor-2-αvβ3 Integrin Cross-talk
Objective: Glycation of proteins of the vessel wall is thought to play an important role in the pathogenesis of vascular complications in diabetes mellitus. However, no previous study has implicated glycated vitronectin (VN) in controlling vascular endothelial growth factor (VEGF) signaling. Therefore, the goal of this study was to investigate the effects of methylglyoxal (MGO)-glycated VN on VEGF signaling. We tested the hypothesis that glycation of VN down-regulates VEGF receptor-2 (VEGFR-2) activation by uncoupling interaction between VEGFR-2 and αvβ3.
Approach and Results: MGO-glycated or unmodified vitronectin were used as substrate for human umbilical vein cells (HUVECs). We studied the effects of glycated VN on VEGF signaling in HUVECs. Glycation of VN inhibited VEGF-induced phosphorylation of VEGFR-2 and intracellular signaling pathway downstream of VEGFR-2. Glycated VN inhibited the binding of VEGFR-2 to β3 integrin and phosphorylation of β3 integrin. LM609 (anti-αvβ3 antibody) inhibited VEGF-induced activation of VEGFR-2 in HUVECs grown on VN. Glycation of VN also significantly decreased VEGF-induced HUVECs migration in vitro and vessel outgrowth in ex vivo angiogenesis model.
Conclusions: Glycation of VN inhibits VEGF-induced VEGFR-2 activation by uncoupling VEGFR-2-αvβ3 integrin cross-talk. Glycation of VN causes a reduction in endothelial cells migration and vessel outgrowth. This may provide a mechanism for the failure of collateral sprouting in diabetic microangiopathy.
Author Disclosures: L. Wang: None. Y. Li: None. N. Chen: None. J. Wu: None.
This research has received full or partial funding support from the American Heart Association.
- © 2015 by American Heart Association, Inc.