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【Arteriosclerosis, Thrombosis, and Vascular Biology】在II
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@vanderbilt.edu
Abstract
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 [标签:content1][标签:content2]
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作者:admin@医学,生命科学 2011-01-16 05:14
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