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

• Published in: International journal of molecular sciences Vol. 23; no. 13; p. 7137
• Main Authors: Zhou, Haiyan, Chen, Tangting, Li, Yongjie, You, Jingcan, Deng, Xin, Chen, Ni, Li, Tian, Zheng, Youkun, Li, Rong, Luo, Mao, Wu, Jianbo, Wang, Liqun
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.07.2022; MDPI
• Subjects: Advanced glycosylation end products; Age; AKT protein; Angiogenesis; Angiopoietin; angiopoietin-1; Aorta; Cell adhesion & migration; Crosslinking; Diabetes; Diabetes mellitus; Endothelial cells; Glycosylation; High fat diet; Hypotheses; Ischemia; Kinases; methylglyoxal; Pathogenesis; Phosphorylation; Proteins; Pyruvaldehyde; Signal transduction; Tie-2; Umbilical vein; Vascular endothelial growth factor
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23137137

The impairment of the angiopoietin-1 (Ang-1)/Tie-2 signaling pathway has been thought to play a critical role in diabetic complications. However, the underlying mechanisms remain unclear. The present study aims to investigate the effects of Tie-2 glycation on Ang-1 signaling activation and Ang-1-induced angiogenesis. We identified that Tie-2 was modified by advanced glycation end products (AGEs) in aortae derived from high fat diet (HFD)-fed mice and in methylglyoxal (MGO)-treated human umbilical vein endothelial cells (HUVECs). MGO-induced Tie-2 glycation significantly inhibited Ang-1-evoked Tie-2 and Akt phosphorylation and Ang-1-regulated endothelial cell migration and tube formation, whereas the blockade of AGE formation by aminoguanidine remarkably rescued Ang-1 signaling activation and Ang-1-induced angiogenesis in vitro. Furthermore, MGO treatment markedly increased AGE cross-linking of Tie-2 in cultured aortae ex vivo and MGO-induced Tie-2 glycation also significantly decreased Ang-1-induced vessel outgrow from aortic rings. Collectively, these data suggest that Tie-2 may be modified by AGEs in diabetes mellitus and that Tie-2 glycation inhibits Ang-1 signaling activation and Ang-1-induced angiogenesis. This may provide a novel mechanism for Ang-1/Tie-2 signal dysfunction and angiogenesis failure in diabetic ischaemic diseases.