title: Impaired autophagy by soluble endoglin, under physiological hypoxia in early pregnant period, is involved in poor placentation in preeclampsia.
abstract: In early pregnancy, trophoblasts and the fetus experience hypoxic and low-nutrient conditions; nevertheless, trophoblasts invade the uterine myometrium up to one third of its depth and migrate along the lumina of spiral arterioles, replacing the maternal endothelial lining. Here, we showed that autophagy, an intracellular bulk degradation system, occurred in extravillous trophoblast (EVT) cells under hypoxia in vitro and in vivo. An enhancement of autophagy was observed in EVTs in early placental tissues, which suffer from physiological hypoxia. The invasion and vascular remodeling under hypoxia were significantly reduced in autophagy-deficient EVT cells compared with wild-type EVT cells. Interestingly, soluble endoglin (sENG), which increased in sera in preeclamptic cases, suppressed EVT invasion by inhibiting autophagy. The sENG-inhibited EVT invasion was recovered by TGFB1 treatment in a dose-dependent manner. A high dose of sENG inhibited the vascular construction by EVT cells and human umbilical vein endothelial cells (HUVECs), meanwhile a low dose of sENG inhibited the replacement of HUVECs by EVT cells. A protein selectively degraded by autophagy, SQSTM1, accumulated in EVT cells in preeclamptic placental biopsy samples showing impaired autophagy. This is the first report showing that impaired autophagy in EVT contributes to the pathophysiology of preeclampsia.
authors: Department of Obstetrics and Gynecology, Faculty of Medicine, University of Toyama, Toyama, Japan.
authors: Akitoshi
authors: A
authors: Nakashima
authors: Mikiko
authors: M
authors: Yamanaka-Tatematsu
authors: Naonobu
authors: N
authors: Fujita
authors: Keiichi
authors: K
authors: Koizumi
authors: Tomoko
authors: T
authors: Shima
authors: Toshiko
authors: T
authors: Yoshida
authors: Toshio
authors: T
authors: Nikaido
authors: Aikou
authors: A
authors: Okamoto
authors: Tamotsu
authors: T
authors: Yoshimori
authors: Shigeru
authors: S
authors: Saito
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D015703:Antigens, CD / Q000097:blood* / Q000502:physiology*; D001343:Autophagy; D015687:Cell Hypoxia; D002460:Cell Line; D049109:Cell Proliferation; D000071063:Endoglin; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D010100:Oxygen / Q000378:metabolism; D010920:Placenta / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000378:metabolism*; D011247:Pregnancy; D011956:Receptors, Cell Surface / Q000097:blood* / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D014327:Trophoblasts / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D049452:Green Fluorescent Proteins; D010100:Oxygen
keywords: SQSTM1; autophagy; extravillous trophoblast; hypoxia; invasion; preeclampsia; soluble endoglin