Gene expression profile of normal and compromised placentas

Abstract

<b>Objective</b> <br>Placenta has an important function of sustaining life in utero. Role of placental gene expression in the physiology of parturition and pathogenesis of pregnancy disorders are poorly understood. The aims of this thesis were to: <br>1. Investigate the effect of labor on global gene expression profile of normal placentas <br>2. Compare placental gene expression profile of uncomplicated pregnancies with that of pregnancies complicated by severe preeclampsia and intrauterine growth restriction (IUGR) <br><b>Materials and Methods</b> <br>Hemodynamic assessment of the maternal uterine and feto-placental circulations was performed ≤72 hours before delivery using Doppler ultrasonography. Global gene expression profile was investigated using microarrays in placental samples collected after delivery from women with normal pregnancies (n=34), and pregnancies complicated by preeclampsia (n=16) and IUGR (n=8). The effect of parturition on gene expression was studied comparing placentas obtained from healthy women after normal delivery (n=17) with placentas obtained from women delivered by elective cesarean section (n=17). Placental gene expression profiles of women with severe preeclampsia (i.e. BP≥160/110 mmHg and proteinuria ≥2+ in dipstick) and IUGR due to placental insufficiency (i.e. estimated fetal weight <5th percentile for the gestational age with hemodynamic signs of redistribution of blood flow to the fetal brain) were compared with healthy controls. Microarray results were validated at the transcript and protein level by real-time reverse-transcriptase polymerase chain reaction (RT-PCR), placental immunofluorescence and urinary electrochemiluminescence immunoassay. <br><b>Results</b> <br>Gene expression profile was similar in healthy placentas obtained following normal delivery and elective cesarean section. Placental genes were differentially expressed in preeclampsia and IUGR compared to normal controls indicating a central role of the placenta in the pathogenesis of these pregnancy-specific disorders. In particular, 16 genes were able to differentiate preeclamptic from normal placentas in our samples after supervised clustering. Several known (leptin, Flt-1, endoglin) and some novel genes (laeverin) and pathways (angiogenesis, hypoxia, Alzheimer, Notch) were found to be involved in the pathogenesis of preeclampsia. Subgroup analysis comparing early- (i.e. ≤34 weeks) with late-onset preeclamptic placentas showed different genetic signatures with oxidative stress, inflammation and endothelin signaling pathways mainly involved in early-onset disease. In IUGR, genes involved in glucocorticoid-metabolism and inflammation mediated by chemokine and cytokine signaling pathway were differentially expressed compared with controls. None of the known imprinted placental genes were differentially expressed. <br><b>Conclusion</b> <br>Labor does not significantly alter the global gene expression profile in near term placenta. Placental gene expression profile is altered in severe preeclampsia and IUGR. Early-onset preeclampsia has a different genetic signature compared with late-onset preeclampsia supporting the possibility of different pathogeneses. Genes involved in inflammatory pathways are up-regulated both in early-onset preeclampsia as well as in IUGR, indicating that they might share common pathogenetic features.