title: Placenta growth factor mediates angiogenesis in hypoxic pulmonary hypertension.
abstract: Our previous studies have proved that hypoxia enhances the 15-lipoxygenase (15-LO) expression and increases endogenous 15-hydroxyeicosatetraenoic acid (15-HETE) production to promote pulmonary vascular remodeling and angiogenesis, while the mechanisms of how hypoxia regulates 15-LO expression in endothelium is still unknown. As placenta growth factor (PlGF) promotes pathological angiogenesis by acting on the growth, migration and survival of endothelial cells, there may be some connections between PlGF and 15-LO in hypoxia induced endothelial cells proliferation. In this study, we performed immunohistochemistry, pulmonary artery endothelial cells migration and bromodeoxyuridine incorporation to determine the role of PlGF in pulmonary remodeling induced by hypoxia. Our results showed that hypoxia up-regulated PlGF expression, which was mediated by 15-LO/15-HETE pathway. Furthermore, we found that PlGF had a positive feedback regulation with 15-LO expression and 15-HETE generation. The interaction in hypoxia between 15-HETE and PlGF created a PlGF-15-LO-15-HETE loop, leading to endothelial dysfunction. Thus, these findings suggest a new therapeutic agent in combination with the blockade of PlGF as well as 15-LO in hypoxic pulmonary hypertension.
authors.affiliation: Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University-Daqing, Daqing 163319, China.
authors.forename: Cui
authors.initials: C
authors.lastname: Ma
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Wang
authors.forename: Tingting
authors.initials: T
authors.lastname: Shen
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Daling
authors.initials: D
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D002417:Cattle; D018797:Cell Cycle Proteins / Q000378:metabolism; D015687:Cell Hypoxia; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology; D004790:Enzyme Induction; D006893:Hydroxyeicosatetraenoic Acids / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D018919:Neovascularization, Physiologic; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000502:physiology*; D021381:Protein Transport; D011651:Pulmonary Artery / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D015533:Transcriptional Activation
chemical_list: D018797:Cell Cycle Proteins; D006893:Hydroxyeicosatetraenoic Acids; C000608038:Pgf protein, rat; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D001093:Arachidonate 15-Lipoxygenase
keywords: 15-Hydroxyeicosatetraenoic acid; 15-Lipoxygenase; Placenta growth factor; Pulmonary arterial hypertension; Pulmonary artery endothelial cell