Preeclampsia-associated stresses activate Gadd45a signaling and sFlt-1 in placental explants.
Accumulating evidence suggests that placental stresses during pregnancy can play an important role in the pathogenesis of preeclampsia. A common signal pathway that senses and converts placental stresses into intracellular stress response may be contributing to this pathology. Based on our previous findings, we extended our investigation to establish that Gadd45a stress signaling regulates sFlt-1 levels, particularly in placenta, when exposed to various preeclampsia-associated stresses including AT-1 receptor agonist (Angiotensin II), hypoxia, and inflammatory cytokines. Using a placental explant model, we found that Gadd45a was induced in response to all the preeclampsia stresses stated above. Although stress induced Gadd45a was associated with the activation of its downstream effectors phospho-p38 and phospho-JNK, the subsequent regulation of sFlt-1 levels occurred through either one of these effectors, but not both. These observations indicate that Gadd45a signaling may work as a hub connecting placental stresses and the pathogenesis of preeclampsia. It also provides evidence to justify testing the role of Gadd45 in the etiology of preeclampsia using in vivo mouse (i.e., Gadd45a null mice) models.
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Yali
Y
Xiong
Dan A
DA
Liebermann
Eliezer J
EJ
Holtzman
Stacey
S
Jeronis
Barbara
B
Hoffman
Ossie
O
Geifman-Holtzman
D000804:Angiotensin II / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000032:analysis; D005260:Female; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000139:chemically induced; D011247:Pregnancy; D015398:Signal Transduction; D013312:Stress, Physiological; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000097642:GADD45 Proteins
D000804:Angiotensin II; D018797:Cell Cycle Proteins; D016207:Cytokines; D048670:MAP Kinase Kinase 4; D009687:Nuclear Proteins; D040281:Vascular Endothelial Growth Factor Receptor-1; D048051:p38 Mitogen-Activated Protein Kinases; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C501162:FLT1 protein, human