Glycation of Tie-2 Inhibits Angiopoietin-1 Signaling Activation and Angiopoietin-1-Induced Angiogenesis

Area of Science:

• Vascular Biology
• Diabetic Complications
• Molecular Mechanisms

Background:

• The angiopoietin-1 (Ang-1)/Tie-2 pathway is crucial for vascular integrity and is implicated in diabetic complications.
• The precise mechanisms by which this pathway is impaired in diabetes remain incompletely understood.

Purpose of the Study:

• To investigate the impact of Tie-2 glycation by advanced glycation end products (AGEs) on Ang-1 signaling activation.
• To determine the effect of Tie-2 glycation on Ang-1-induced angiogenesis in vitro and ex vivo.

Main Methods:

• Identification of Tie-2 modification by AGEs in high-fat diet (HFD)-fed mice aortae and methylglyoxal (MGO)-treated human umbilical vein endothelial cells (HUVECs).
• Assessment of Ang-1 signaling activation (Tie-2 and Akt phosphorylation) and endothelial cell functions (migration, tube formation) following MGO treatment.
• Evaluation of the protective effects of aminoguanidine (AGE formation blockade) on Ang-1 signaling and angiogenesis.
• Analysis of AGE cross-linking of Tie-2 and Ang-1-induced vessel outgrowth from aortic rings ex vivo.

Main Results:

• Tie-2 was found to be modified by AGEs in HFD-fed mice and MGO-treated HUVECs.
• MGO-induced Tie-2 glycation significantly inhibited Ang-1-evoked Tie-2/Akt phosphorylation, endothelial cell migration, and tube formation.
• Aminoguanidine treatment rescued Ang-1 signaling and angiogenesis, demonstrating the role of AGEs.
• MGO treatment increased Tie-2 AGE cross-linking and reduced Ang-1-induced vessel outgrowth from aortic rings ex vivo.

Conclusions:

• Tie-2 is susceptible to AGE modification in the context of diabetes mellitus.
• Tie-2 glycation disrupts Ang-1 signaling, leading to impaired angiogenesis.
• This glycation-induced Tie-2 dysfunction presents a novel mechanism contributing to angiogenesis failure in diabetic ischemic diseases.