Abstract
Preeclampsia (PE) is known to be associated with increased circulating levels of anti-angiogenic factors, such as soluble fms-related tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng). However, the way that placental oxidative stress results in the elevation of these two factors remains enigmatic. We have observed the overexpression of growth arrest and DNA damage-inducible 45 alpha (Gadd45α) and excessive activation of p38 mitogen-activated protein kinase (MAPK) in preeclamptic placentas compared with normotensive controls, together with increased levels of sFlt-1 and sEng in maternal sera in patients with PE. Moreover, Gadd45α knockdown or p38 inhibition provides protective effects in hypoxia/reoxygenation (H/R)-exposed human umbilical vein endothelial cells (HUVECs) by suppressing oxidative stress, inhibiting apoptosis, and promoting their potential for in vitro angiogenesis. A regulatory signaling pathway in which H/R intervention causes the induction of Gadd45α leading to p38 activation and ultimately an increase in sFlt-1 and sEng secretion in HUVECs has concurrently been established. Our study opens up a promising new avenue of investigation for increasing the understanding of the origin of sFlt-1 and sEng in PE and provides novel therapeutic targets for pregnancy complications arising from placental endothelial dysfunction.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Antigens, CD / blood
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Antigens, CD / metabolism*
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Apoptosis / physiology
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Cell Cycle Proteins / antagonists & inhibitors
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Hypoxia / physiology
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Endoglin
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Endothelial Cells / metabolism
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Enzyme Activation
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Female
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Gene Knockdown Techniques
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Humans
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Immunohistochemistry
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MAP Kinase Signaling System
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Oxidative Stress / physiology
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Pre-Eclampsia / blood
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Pre-Eclampsia / enzymology
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Pre-Eclampsia / metabolism*
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Pregnancy
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RNA, Small Interfering / administration & dosage
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RNA, Small Interfering / genetics
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Reactive Oxygen Species / metabolism
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Receptors, Cell Surface / blood
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Receptors, Cell Surface / metabolism*
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Transfection
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Up-Regulation
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Vascular Endothelial Growth Factor Receptor-1 / blood
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Vascular Endothelial Growth Factor Receptor-1 / metabolism*
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / metabolism*
Substances
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Antigens, CD
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Cell Cycle Proteins
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ENG protein, human
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Endoglin
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GADD45A protein, human
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Nuclear Proteins
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RNA, Small Interfering
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Reactive Oxygen Species
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Receptors, Cell Surface
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FLT1 protein, human
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Vascular Endothelial Growth Factor Receptor-1
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p38 Mitogen-Activated Protein Kinases