title: Role for the thromboxane A2 receptor β-isoform in the pathogenesis of intrauterine growth restriction.
abstract: Intrauterine growth restriction (IUGR) is a pathology of pregnancy that results in failure of the fetus to reach its genetically determined growth potential. In developed nations the most common cause of IUGR is impaired placentation resulting from poor trophoblast function, which reduces blood flow to the fetoplacental unit, promotes hypoxia and enhances production of bioactive lipids (TXA2 and isoprostanes) which act through the thromboxane receptor (TP). TP activation has been implicated as a pathogenic factor in pregnancy complications, including IUGR; however, the role of TP isoforms during pregnancy is poorly defined. We have determined that expression of the human-specific isoform of TP (TPβ) is increased in placentae from IUGR pregnancies, compared to healthy pregnancies. Overexpression of TPα enhanced trophoblast proliferation and syncytialisation. Conversely, TPβ attenuated these functions and inhibited migration. Expression of the TPβ transgene in mice resulted in growth restricted pups and placentae with poor syncytialisation and diminished growth characteristics. Together our data indicate that expression of TPα mediates normal placentation; however, TPβ impairs placentation, and promotes the development of IUGR, and represents an underappreciated pathogenic factor in humans.
authors.affiliation: Division of Perinatal Research, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, 2065, Australia.|Sydney Medical School Northern, University of Sydney, NSW, 2006, Australia.|Pathology North, NSW Health Pathology, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia.
authors.forename: Katie L
authors.initials: KL
authors.lastname: Powell
authors.affiliation: Division of Perinatal Research, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, 2065, Australia.|Sydney Medical School Northern, University of Sydney, NSW, 2006, Australia.
authors.forename: Veronica
authors.initials: V
authors.lastname: Stevens
authors.affiliation: Division of Perinatal Research, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, 2065, Australia.|School of Life Sciences, University of Technology Sydney, Ultimo, NSW, 2007, Australia.
authors.forename: Dannielle H
authors.initials: DH
authors.lastname: Upton
authors.affiliation: Division of Perinatal Research, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, 2065, Australia.|Sydney Medical School Northern, University of Sydney, NSW, 2006, Australia.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: McCracken
authors.affiliation: School of Life Sciences, University of Technology Sydney, Ultimo, NSW, 2007, Australia.|Centre for Health Technologies, University of Technology Sydney, Ultimo, NSW, 2007, Australia.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Simpson
authors.affiliation: Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Division of Perinatal Research, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, 2065, Australia.|Pathology North, NSW Health Pathology, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia.|School of Life Sciences, University of Technology Sydney, Ultimo, NSW, 2007, Australia.
authors.forename: Vitomir
authors.initials: V
authors.lastname: Tasevski
authors.affiliation: Division of Perinatal Research, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, 2065, Australia.|Sydney Medical School Northern, University of Sydney, NSW, 2006, Australia.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Morris
authors.affiliation: Division of Perinatal Research, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, 2065, Australia.|Sydney Medical School Northern, University of Sydney, NSW, 2006, Australia.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Ashton
mesh_terms: D000328:Adult; D000818:Animals; D000831:Animals, Newborn; D045744:Cell Line, Tumor; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000235:genetics / Q000378:metabolism; D013928:Thromboxane A2 / Q000378:metabolism; D014327:Trophoblasts / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013928:Thromboxane A2