title: Nogo-B receptor modulates angiogenesis response of pulmonary artery endothelial cells through eNOS coupling.
abstract: 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.
authors.affiliation: Departments of 1 Pediatrics.
authors.forename: Ru-Jeng
authors.initials: RJ
authors.lastname: Teng
authors.forename: Ujala
authors.initials: U
authors.lastname: Rana
authors.forename: Adeleye J
authors.initials: AJ
authors.lastname: Afolayan
authors.forename: Baofeng
authors.initials: B
authors.lastname: Zhao
authors.forename: Qing R
authors.initials: QR
authors.lastname: Miao
authors.forename: Girija G
authors.initials: GG
authors.lastname: Konduri
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology*; D006136:GTP Cyclohydrolase / Q000378:metabolism; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D000070798:Nogo Proteins; D010547:Persistent Fetal Circulation Syndrome / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011651:Pulmonary Artery / Q000201:enzymology* / Q000503:physiopathology; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D012756:Sheep; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism; D014162:Transfection
chemical_list: D009185:Myelin Proteins; C512614:NUS1 protein, human; D000070798:Nogo Proteins; C000603199:RTN4 protein, human; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase; D051057:Proto-Oncogene Proteins c-akt; D006136:GTP Cyclohydrolase
keywords: Nogo-B; Nogo-B receptor; angiogenesis; intrauterine pulmonary hypertension; pulmonary artery endothelial cells