Nogo-B receptor modulates angiogenesis response of pulmonary artery endothelial cells through eNOS coupling

• Published in: American journal of respiratory cell and molecular biology Vol. 51; no. 2; pp. 169 - 177
• Main Authors: Teng, Ru-Jeng, Rana, Ujala, Afolayan, Adeleye J, Zhao, Baofeng, Miao, Qing R, Konduri, Girija G
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.08.2014
• Subjects: Angiogenesis; Animals; Cell adhesion & migration; Cells, Cultured; Defects; Disease Models, Animal; Endothelial Cells - enzymology; GTP Cyclohydrolase - metabolism; Lungs; Musculoskeletal system; Myelin Proteins - genetics; Myelin Proteins - metabolism; Neovascularization, Physiologic; Nervous system; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - metabolism; Nogo Proteins; Original Research; Persistent Fetal Circulation Syndrome - enzymology; Persistent Fetal Circulation Syndrome - genetics; Persistent Fetal Circulation Syndrome - physiopathology; Phosphorylation; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Pulmonary arteries; Pulmonary Artery - enzymology; Pulmonary Artery - physiopathology; Pulmonary hypertension; Reactive Oxygen Species - metabolism; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; RNA Interference; Sheep; Signal Transduction; Smooth muscle; Superoxide Dismutase - metabolism; Transfection; Vascular endothelial growth factor; Veins & arteries; Nogo-B; intrauterine pulmonary hypertension; Nogo-B receptor; pulmonary artery endothelial cells; angiogenesis
• ISSN: 1044-1549; 1535-4989
• DOI: 10.1165/rcmb.2013-0298OC

Nogo-B, a reticulon-4 isoform, modulates the motility and adhesion of vascular endothelial cells after binding to its receptor, Nogo-B receptor (NgBR). Nogo-B/NgBR pathway contributes to vascular remodeling and angiogenesis, but the role of this pathway in the angiogenesis of developing lungs remains unknown. We previously reported that angiogenesis function of pulmonary artery endothelial cells (PAECs) is impaired by increased reactive oxygen species formation in a fetal lamb model of intrauterine pulmonary hypertension (IPH). Here, we report that Nogo-B/NgBR pathway is altered in IPH, and that decreased NgBR expression contributes to impaired angiogenesis in IPH. We observed a decrease in NgBR levels in lysates of whole lung or PAECs from fetal lambs with IPH compared with controls. Overexpression of NgBR in IPH PAECs rescued the in vitro angiogenesis defects and increased the phosphorylation of both Akt and endothelial nitric oxide synthase at serine(1179) as well as the levels of both manganese superoxide dismutase and GTP cyclohydrolase-1. Consistent with the phenotype of IPH PAECs, knockdown of NgBR in control PAECs decreased the levels of nitric oxide, increased the levels of reactive oxygen species, and impaired in vitro angiogenesis. Our data demonstrate that NgBR mediates PAEC angiogenesis response through the modulation of Akt/endothelial nitric oxide synthase functions, and its decreased expression is mechanistically linked to IPH-related angiogenesis defects in the developing lungs.