title: Activation of villous trophoblastic p38 and ERK1/2 signaling pathways in preterm preeclampsia and HELLP syndrome.
abstract: Preterm preeclampsia is associated with the failure of trophoblast invasion, placental hypoxic/ischemic injury and the release of toxic substances, which promote the terminal pathway of preeclampsia. In term preeclampsia, factors yet unknown trigger the placenta to induce the terminal pathway. The contribution of the villous trophoblast to these pathologic events has not been fully elucidated. Here we aimed to study how stress and signaling pathways influence trophoblastic functions in various subforms of preeclampsia. Tissue microarrays (TMAs) were constructed from placentas obtained from pregnant women in the following groups: 1-2) preterm preeclampsia with (n = 8) or without (n = 7) HELLP syndrome; 3) late-onset preeclampsia (n = 8); 4-5) preterm (n = 5) and term (n = 9) controls. TMA slides were stained for phosphorylated Akt-1, ERK1/2, JNK, and p38 kinases, and trophoblastic immunostainings were semi-quantitatively evaluated. BeWo cells were kept in various stress conditions, and the expression of FLT1, GCM1, LEP, and PGF was profiled by qRT-PCR, while Akt-1, ERK1/2, JNK, and p38 kinase activities were measured with phospho-kinase immunoassays. We found that: 1) Placental LEP and FLT1 expression was up-regulated in preterm preeclampsia with or without HELLP syndrome compared to controls; 2) Mean pp38 immunoscore was higher in preterm preeclampsia, especially in cases with HELLP syndrome, than in controls. 3) Mean pERK1/2 immunoscore was higher in preterm preeclampsia with HELLP syndrome than in controls. 4) In BeWo cells, ischemia up-regulated LEP expression, and it increased JNK and decreased ERK1/2 activity. 5) Hypoxia up-regulated FLT1 and down-regulated PGF expression, and it increased ERK1/2, JNK and p38 activity. 6) IL-1β treatment down-regulated PGF expression, and it increased JNK and p38 activity. 7) The p38 signaling pathway had the most impact on LEP, FLT1 and PGF expression. In conclusion, hypoxic and ischemic stress, along with unknown factors, activates trophoblastic p38 signaling, which has a key role in villous trophoblastic functional changes in preterm preeclampsia. The activation of ERK1/2 signaling may induce additional trophoblastic functional changes in HELLP syndrome, while distinct mechanisms may promote late-onset preeclampsia.
authors.affiliation: Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, Budapest, Hungary.
authors.forename: Szilvia
authors.initials: S
authors.lastname: Szabo
authors.forename: Meera
authors.initials: M
authors.lastname: Mody
authors.forename: Roberto
authors.initials: R
authors.lastname: Romero
authors.forename: Yi
authors.initials: Y
authors.lastname: Xu
authors.forename: Katalin
authors.initials: K
authors.lastname: Karaszi
authors.forename: Noemi
authors.initials: N
authors.lastname: Mihalik
authors.forename: Zhonghui
authors.initials: Z
authors.lastname: Xu
authors.forename: Gaurav
authors.initials: G
authors.lastname: Bhatti
authors.forename: Tibor
authors.initials: T
authors.lastname: Fule
authors.forename: Petronella
authors.initials: P
authors.lastname: Hupuczi
authors.forename: Tibor
authors.initials: T
authors.lastname: Krenacs
authors.forename: Janos
authors.initials: J
authors.lastname: Rigo
authors.forename: Adi L
authors.initials: AL
authors.lastname: Tarca
authors.forename: Sonia S
authors.initials: SS
authors.lastname: Hassan
authors.forename: Tinnakorn
authors.initials: T
authors.lastname: Chaiworapongsa
authors.forename: Ilona
authors.initials: I
authors.lastname: Kovalszky
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Papp
authors.forename: Nandor Gabor
authors.initials: NG
authors.lastname: Than
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002824:Chorionic Villi / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D017359:HELLP Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D007124:Immunoenzyme Techniques; D007231:Infant, Newborn; D007511:Ischemia / Q000503:physiopathology; D020935:MAP Kinase Signaling System; D010920:Placenta / Q000378:metabolism* / Q000473:pathology; D011225:Pre-Eclampsia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D047928:Premature Birth; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D014327:Trophoblasts / Q000378:metabolism* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D048051:p38 Mitogen-Activated Protein Kinases