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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1606.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Disruption of Ang-1/Tie-2 Signaling Contributes to the Impaired Myocardial Vascular Maturation and Angiogenesis in Type II Diabetic Mice

Jian-Xiong Chen; Amanda Stinnett

From the Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, Tenn.

Correspondence to Jian-Xiong Chen, MD, Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, MRB IV-1125, Nashville, TN 37232-2650. E-mail Jian-xiong.chen{at}vanderbilt.edu

Objective— Microvascular 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 Results— Tie-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.

Conclusions— Our findings underscore the important role of Ang-1–Tie-2 signaling in the diabetes-induced impairment of vascular maturation and angiogenesis.

Key Words: hyperglycemia • angiopoietins/Tie-2 • myocardial ischemia • angiogenesis • type II diabetes

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