Disruption of Ang-1/Tie-2 signaling contributes to the impaired myocardial vascular maturation and angiogenesis in type II diabetic mice.
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.


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.
Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, MRB IV-1125, Nashville, TN 37232-2650, USA. Jian-xiong.chen@vanderbilt.edu
Jian-Xiong
JX
Chen
Amanda
A
Stinnett
D042683:Angiopoietin-1 / Q000378:metabolism*; D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D002465:Cell Movement; D003331:Coronary Vessels / Q000378:metabolism* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000378:metabolism / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D046509:Tissue Culture Techniques
D042683:Angiopoietin-1; D042702:Angiopoietin-2; C467628:Angpt1 protein, mouse; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D042787:Receptor, TIE-2; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose