Activation of Villous Trophoblastic p38 and ERK1/2 Signaling Pathways in Preterm Preeclampsia and HELLP Syndrome

Szilvia Szabo, Meera Mody, Roberto Romero, Yi Xu, Katalin Karaszi, Noemi Mihalik, Zhonghui Xu, Gaurav Bhatti, T. Füle, P. Hupuczi, T. Krenács, J. Rigó, Adi L. Tarca, Sonia S. Hassan, Tinnakorn Chaiworapongsa, I. Kovalszky, Z. Papp, Nandor Gabor Than

Research output: Article

18 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)659-668
Number of pages10
JournalPathology and Oncology Research
Volume21
Issue number3
DOIs
Publication statusPublished - júl. 5 2015

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HELLP Syndrome
MAP Kinase Signaling System
Pre-Eclampsia
Prostaglandins F
MAP Kinase Kinase 4
Trophoblasts
Placenta
Poisons
Interleukin-1
Immunoassay
Pregnant Women
Phosphotransferases
Ischemia

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pathology and Forensic Medicine

Cite this

Activation of Villous Trophoblastic p38 and ERK1/2 Signaling Pathways in Preterm Preeclampsia and HELLP Syndrome. / Szabo, Szilvia; Mody, Meera; Romero, Roberto; Xu, Yi; Karaszi, Katalin; Mihalik, Noemi; Xu, Zhonghui; Bhatti, Gaurav; Füle, T.; Hupuczi, P.; Krenács, T.; Rigó, J.; Tarca, Adi L.; Hassan, Sonia S.; Chaiworapongsa, Tinnakorn; Kovalszky, I.; Papp, Z.; Than, Nandor Gabor.

In: Pathology and Oncology Research, Vol. 21, No. 3, 05.07.2015, p. 659-668.

Research output: Article

Szabo, S, Mody, M, Romero, R, Xu, Y, Karaszi, K, Mihalik, N, Xu, Z, Bhatti, G, Füle, T, Hupuczi, P, Krenács, T, Rigó, J, Tarca, AL, Hassan, SS, Chaiworapongsa, T, Kovalszky, I, Papp, Z & Than, NG 2015, 'Activation of Villous Trophoblastic p38 and ERK1/2 Signaling Pathways in Preterm Preeclampsia and HELLP Syndrome', Pathology and Oncology Research, vol. 21, no. 3, pp. 659-668. https://doi.org/10.1007/s12253-014-9872-9
Szabo, Szilvia ; Mody, Meera ; Romero, Roberto ; Xu, Yi ; Karaszi, Katalin ; Mihalik, Noemi ; Xu, Zhonghui ; Bhatti, Gaurav ; Füle, T. ; Hupuczi, P. ; Krenács, T. ; Rigó, J. ; Tarca, Adi L. ; Hassan, Sonia S. ; Chaiworapongsa, Tinnakorn ; Kovalszky, I. ; Papp, Z. ; Than, Nandor Gabor. / Activation of Villous Trophoblastic p38 and ERK1/2 Signaling Pathways in Preterm Preeclampsia and HELLP Syndrome. In: Pathology and Oncology Research. 2015 ; Vol. 21, No. 3. pp. 659-668.
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T1 - Activation of Villous Trophoblastic p38 and ERK1/2 Signaling Pathways in Preterm Preeclampsia and HELLP Syndrome

AU - Szabo, Szilvia

AU - Mody, Meera

AU - Romero, Roberto

AU - Xu, Yi

AU - Karaszi, Katalin

AU - Mihalik, Noemi

AU - Xu, Zhonghui

AU - Bhatti, Gaurav

AU - Füle, T.

AU - Hupuczi, P.

AU - Krenács, T.

AU - Rigó, J.

AU - Tarca, Adi L.

AU - Hassan, Sonia S.

AU - Chaiworapongsa, Tinnakorn

AU - Kovalszky, I.

AU - Papp, Z.

AU - Than, Nandor Gabor

PY - 2015/7/5

Y1 - 2015/7/5

N2 - 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.

AB - 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.

KW - Anti-angiogenic factor

KW - Hypertension

KW - Mitogen activated protein kinase

KW - Oxidative stress

KW - Pregnancy

KW - Signal transduction

KW - Syncytiotrophoblast

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