Angiopoietin-1-induced angiogenesis is modulated by endothelial NADPH oxidase.

Chen JX, Zeng H, Lawrence ML, Blackwell TS, Meyrick B
Am J Physiol Heart Circ Physiol. 2006 291 (4): H1563-72

PMID: 16679392 · DOI:10.1152/ajpheart.01081.2005

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 min led to a transient and dose-dependent increase in intracellular ROS. Thirty minutes of pretreatment with the NADPH oxidase inhibitors diphenylene iodinium (DPI, 10 microM) and apocynin (200 microM) 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 wild-type (WT) mice and mice deficient in the p47(phox) component of NADPH oxidase (p47(phox-/-)), we found that although 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 p47(phox-/-) mice. Furthermore, exposure of aortic rings from p47(phox-/-) 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.

MeSH Terms (20)

Acetophenones Angiopoietin-1 Animals Cell Movement Cells, Cultured Endothelium, Vascular Enzyme Inhibitors Gene Expression Regulation, Enzymologic Mice Mice, Knockout Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 NADPH Oxidases Neovascularization, Physiologic Oncogene Protein v-akt Onium Compounds Phosphorylation Reactive Oxygen Species Receptor, TIE-2 Swine

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