Impairment of Angiogenic Sphingosine Kinase-1/Sphingosine-1-Phosphate Receptors Pathway in Preeclampsia.
Preeclampsia (PE), is a serious pregnancy disorder characterized in the early gestation by shallow trophoblast invasion, impaired placental neo-angiogenesis, placental hypoxia and ischemia, which leads to maternal and fetal morbidity and mortality. Here we hypothesized that angiogenic sphingosine kinase-1 (SPHK1)/sphingosine-1-phosphate (S1P) receptors pathway is impaired in PE. We found that SPHK1 mRNA and protein expression are down-regulated in term placentae and term chorionic villous explants from patients with PE or severe PE (PES), compared with controls. Moreover, mRNA expression of angiogenic S1PR1 and S1PR3 receptors were decreased in placental samples of PE and PES patients, whereas anti-angiogenic S1PR2 was up-regulated in chorionic villous tissue of PES subjects, pointing to its potential atherogenic and inflammatory properties. Furthermore, in in vitro (JAR cells) and ex vivo (chorionic villous explants) models of placental hypoxia, SPHK1 mRNA and protein were strongly up-regulated under low oxygen tension (1% 02). In contrast, there was no change in SPHK1 expression under the conditions of placental physiological hypoxia (8% 02). In both models, nuclear protein levels of HIF1A were increased at 1% 02 during the time course, but there was no up-regulation at 8% 02, suggesting that SPHK1 and HIF1A might be the part of the same canonical pathway during hypoxia and that both contribute to placental neovascularization during early gestation. Taken together, this study suggest the SPHK1 pathway may play a role in the human early placentation process and may be involved in the pathogenesis of PE.
Department of Obstetrics & Gynecology and Laboratory of Reproductive Biology, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
Aneta
A
Dobierzewska
Department of Obstetrics & Gynecology and Laboratory of Reproductive Biology, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
Macarena
M
Palominos
Department of Obstetrics & Gynecology and Laboratory of Reproductive Biology, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
Marianela
M
Sanchez
Department of Obstetrics & Gynecology and Laboratory of Reproductive Biology, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
Michael
M
Dyhr
Department of Obstetrics & Gynecology and Laboratory of Reproductive Biology, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
Katja
K
Helgert
Department of Obstetrics & Gynecology and Laboratory of Reproductive Biology, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
Pia
P
Venegas-Araneda
Translational Obstetrics Group, Department of Obstetrics and Gynecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
Stephen
S
Tong
Department of Obstetrics & Gynecology and Laboratory of Reproductive Biology, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.|Department of Maternal-Fetal Medicine, Clinica Davila, Santiago, Chile.
Sebastian E
SE
Illanes
D000328:Adult; D015687:Cell Hypoxia; D002460:Cell Line; D015536:Down-Regulation; D005260:Female; D006801:Humans; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism / Q000473:pathology*; D010929:Placentation; D011225:Pre-Eclampsia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011247:Pregnancy; D049349:Receptors, Lysosphingolipid / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014327:Trophoblasts / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation; D000099157:Sphingosine Kinase
D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D000099157:Sphingosine Kinase