期刊
PLACENTA
卷 36, 期 8, 页码 809-820出版社
W B SAUNDERS CO LTD
DOI: 10.1016/j.placenta.2015.04.008
关键词
Laminin; LAMA4; Placenta; Trophoblast; Preeclampsia; MAPK; p38; JNK; ERK; Methylation
资金
- National Natural Science Foundation of China [81070502, 81170585, 81100444, 81300509, 81300508]
- National Key Clinical Department of China
Introduction: The laminin all subunit (LAMA4) has been shown to promote migration, proliferation, and survival of various cell types. This study investigated LAMA4's role in trophoblast cells during placental development. Methods: LAMA4 expression was immunohistochemically assessed in the first trimester and term human placentas. LAMA4 siRNA was applied to silence LAMA4 expression in extravillous explants and HTR8/ SVneo cells. Hypoxia-reoxygenation (H/R) conditions were applied to mimic preeclampsia. LAMA4 expression and trophoblast cell invasion, migration, and tube formation (a measure of angiogenesis) were assessed in HTR8/SVneo cells. The p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 was used to study the mechanism underlying LAMA4 activity. LAMA4 promoter methylation was assessed by bisulfite-sequencing polymerase chain reaction (PCR) or methylation-specific PCR. Results: LAMA4 levels in preeclamptic placentas were significantly lower than those in controls. LAMA4 silencing significantly inhibited extravillous explant outgrowth as well as HTR8/SVneo cell invasion and migration. H/R conditions significantly lowered LAMA4 expression. Application of either H/R conditions or LAMA4 silencing both significantly decreased HTR8/SVneo cell invasion, migration, and tube formation, decreased MMP2 and MMP9 expression, and increased TIMP2 expression. SB203580 significantly reduced LAMA4 expression. LAMA4 silencing significantly decreased p-p38, p-c-Jun N-terminal kinase (JNK), and p-extracellular signal-regulated kinase (ERK) expressions; by contrast, H/R conditions induced significant upregulation of p-p38 and p-ERK but decreased p-JNK. LAMA4 promoter methylation was not significantly altered in preeclamptic placentas compared to controls. Conclusions: LAMA4 expression is lowered in preeclamptic placentas and promotes trophoblast cell invasion, migration, and angiogenesis. H/R conditions decrease LAMA4 expression and appear to decouple the positive relationship between LAMA4 expression and p38 and ERK activation. (C) 2015 Published by Elsevier Ltd.
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