• Jian-Xiong Chen and Amanda Stinnett.
• Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, MRB IV-1125, Nashville, TN 37232-2650, USA. Jian-xiong.chen@vanderbilt.edu
• Arterioscler. Thromb. Vasc. Biol. 2008 Sep 1; 28 (9): 1606-13.

ObjectiveMicrovascular insufficiency represents a major cause of end-organ failure among diabetics. The current studies were undertaken to determine whether dysregulation of the angiopoietins/Tie-2 system would result in an impairment of smooth muscle cell (SMC) recruitment and vascular maturation, which contributes to impaired angiogenesis in diabetes.Methods And ResultsTie-2 expression was significantly attenuated, whereas angiopoietin-2 (Ang-2) was increased in db/db mice subjected to myocardial ischemia. Our morphological analysis showed that the number of SMC coverage area per neovessel was significantly reduced in db/db mice. This was accompanied by a significant reduction of myocardial capillary density and arteriole formation. Interestingly, Angiopoietin-1(Ang-1)-induced SMC recruitment and vessel outgrowth were severely impaired in db/db mice. Our in vitro studies further demonstrated that exposure of mouse heart endothelial cells to high glucose resulted in a significant upregulation of Ang-2 and a downregulation of Tie-2 expression. These alterations led to a significant impairment of Ang-1-induced Akt and eNOS phosphorylation, along with a remarkable impairment of Ang-1-induced endothelial cell migration and endothelial cell spheroid sprouting. Ang-1 gene transfer restored Tie-2 expression and rescued these abnormalities in diabetes.ConclusionsOur findings underscore the important role of Ang-1-Tie-2 signaling in the diabetes-induced impairment of vascular maturation and angiogenesis.

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