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.

The chimera‐type galectin‐3 is a positive modulator of trophoblast functions with dysregulated expression in gestational diabetes mellitus

“…Immunohistochemistry was performed on formalin‐fixed, paraffin‐embedded placental tissues as previously described 18 . Briefly, 4 µm sections derived from the first trimester and term placenta biopsies derived from normal pregnancy were dewaxed and rehydrated through graded alcohols.…”

“…Immunohistochemistry was performed on formalin-fixed, paraffinembedded placental tissues as previously described. 18 Briefly, 4 µm sections derived from the first trimester and term placenta biopsies derived from normal pregnancy were dewaxed and rehydrated through graded alcohols. Antigen retrieval was performed at 99°C for 20 min in a pH9 retrieval solution, and slides were incubated in Sequenza racks with primary antibody gal-3 (0.5 µg/mL; Santa Cruz Biotechnology sc-32790), cytokeratin 7 (0.09 µg/mL; Abcam ab68459), mouse IgG1 isotype control (Dako) or rabbit monoclonal antibody (Cell Signaling Technology) at equivalent concentrations at 4°C for 18 hours.…”

Galectin-3 deficiency in pregnancy increases the risk of fetal growth restriction (FGR) via placental insufficiency

“…As suspected, gal-3 peripheral levels were found to correlate inversely with Ut PI values (r s = −0.5065, P < 0.05) in pregnancies complicated with FGR. In addition, we used placental biopsies taken at birth from uneventful (n = 27) and FGR pregnancies with placental pathology (n = 19) in an independent cohort recruited in Australia (clinical data shown in Supplementary information, 18 ). Similar to our observations in mice, FGR placentas expressed decreased protein levels of gal-3 in general as revealed by western blot (Fig.…”

“…For analyses of gal-3 expression in pregnancy affected only by FGR, patient samples from the research bio-bank collection at the Kolling Institute, Sydney, Australia were used. Use was approved by the Northern Sydney Local Health District Human research Ethics Committee, (St Leonards, NSW, Australia) and was assigned the sitespecific assessment number 0912-348 M and the Australian national ethics application form number HREC/ 09/HARBR/165 as described 18 .…”

Dysregulation of Oxygen Sensing/Response Pathways in Pregnancies Complicated by Idiopathic Intrauterine Growth Restriction and Early-Onset Preeclampsia

“…Sections (4 μm) of paraffin-embedded placental tissue were stained as described [ 52 ] with antigen retrieval at pH6.0 for 20 min. Sections were incubated with antibodies against HIF-1α (Abcam, Cambridge, UK) at 2 μg/mL over night at 4 °C.…”