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1 Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
2 Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
3 Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, United States; Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
* To whom correspondence should be addressed. E-mail: barbara.meyrick{at}vanderbilt.edu.
Reactive oxygen species (ROS) play a central role in the pathogenesis of many cardiovascular diseases such as atherosclerosis and hypertension. Endothelial NADPH oxidase is the major source of intracellular ROS. The present study investigated the role of endothelial NADPH oxidase-derived ROS in Angiopoietin-1 (Ang-1) -induced angiogenesis. Exposure of porcine coronary artery endothelial cells (PCAECs) to Ang-1 (250 ng/ml) for periods up to 30 minutes led to a transient and dose-dependent increase in intracellular ROS. Thirty minutes pretreatment with the NADPH oxidase inhibitors, diphenylene iodinium (DPI, 10 |*mu*M) and apocynin (200 µM) suppressed Ang-1-stimulated ROS. Pretreatment with either DPI or apocynin also significantly attenuated Ang-1-induced Akt and p44/42 MAPK phosphorylation. In addition, inhibition of NADPH oxidase significantly suppressed Ang-1-induced endothelial cell migration and sprouting from endothelial spheroids. Using mouse heart microvascular endothelial cells from WT and mice deficient in the p47phox component of NADPH oxidase (p47phox -/-), we found that while Ang-1-stimulated intracellular ROS, Akt and p42/44 MAPK phosphorylation, and cell migration in WT cells; the responses were strikingly suppressed in cells from the p47phox -/- mice. Further, exposure of aortic rings from p47phox-/- mice to Ang-1 demonstrated fewer vessel sprouts than WT mice. Inhibition of the Tie-2 receptor inhibited Ang-1-induced endothelial migration and vessel sprouting. Together, our data strongly suggest that endothelial NADPH oxidase-derived ROS play a critical role in Ang-1-induced angiogenesis.
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