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.

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“…Additionally, if sVEGFR1 and soluble endoglin are given to pregnant rats, the animals not only develop preeclampsia but also liver dysfunction, thrombocytopenia, and intrauterine growth restriction(124); similar results have been obtained in mice(141). This condition is indistinguishable from the HELLP syndrome observed in humans(181–184). …”

Akt/mTOR Role in Human Foetoplacental Vascular Insulin Resistance in Diseases of Pregnancy

“…Preferential activation of p42/44 mapk and Akt is described in the foetoplacental vasculature from PE. Preterm PE (<37 wg) with HELLP (Hemolysis, Elevated Liver enzymes, and Low Platelet count) courses with increased phosphorylated p42/44 mapk activation in villous trophoblast [ 57 ]. In addition, the maternal plasma level from women with EOPE shows a higher level of endothelin-1 (ET-1) [ 58 ], but reduced Akt activity in the placenta [ 59 ] ( Figure 3 ).…”

Deregulation of c‐Src tyrosine kinase and its downstream targets in pre‐eclamptic placenta

“…Furthermore, a recent study also revealed that p38 phosphorylation was upregulated in PE placentas . Interestingly, a study reported that p38 phosphorylation was increased in preterm pre‐eclampsia, but remained unchanged in late onset pre‐eclampsia . It must be borne in mind that our data was generated using two distinct groups of control and PE women.…”