abnormalities in oxygen sensing define early and late onset preeclampsia as distinct pathologies异常氧气传感发病早期和晚期子痫前期定义为明显的病态.pdfVIP

Abnormalities in Oxygen Sensing Define Early and Late Onset Preeclampsia as Distinct Pathologies 1 1 1,3 1 1 1 Alessandro Rolfo , Ariel Many , Antonella Racano , Reshef Tal , Andrea Tagliaferro , Francesca Ietta , Jinxia Wang5, Martin Post3,4,5, Isabella Caniggia1,2,3,4* 1 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, 2 Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada, 3 Department of Physiology, University of Toronto, Toronto, Ontario, Canada, 4 Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada, 5 The Hospital for Sick Children, Toronto, Ontario, Canada Abstract Background: The pathogenesis of preeclampsia, a serious pregnancy disorder, is still elusive and its treatment empirical. Hypoxia Inducible Factor-1 (HIF-1) is crucial for placental development and early detection of aberrant regulatory mechanisms of HIF-1 could impact on the diagnosis and management of preeclampsia. HIF-1a stability is controlled by O2- sensing enzymes including prolyl hydroxylases (PHDs), Factor Inhibiting HIF (FIH), and E3 ligases Seven In Absentia Homologues (SIAHs). Here we investigated early- (E-PE) and late-onset (L-PE) human preeclamptic placentae and their ability to sense changes in oxygen tension occurring during normal placental development. Methods and Findings: Expression of PHD2, FIH and SIAHs were significantly down-regulated in E-PE compared to control and L-PE placentae, while HIF-1a levels were increased. PHD3 expression was increased due to decreased FIH levels as demonstrated by siRNA F