Abnormalities in oxygen sensing define early and late onset preeclampsia as distinct pathologies.
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-1α stability is controlled by O(2)-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.


RESULTS
Expression of PHD2, FIH and SIAHs were significantly down-regulated in E-PE compared to control and L-PE placentae, while HIF-1α levels were increased. PHD3 expression was increased due to decreased FIH levels as demonstrated by siRNA FIH knockdown experiments in trophoblastic JEG-3 cells. E-PE tissues had markedly diminished HIF-1α hydroxylation at proline residues 402 and 564 as assessed with monoclonal antibodies raised against hydroxylated HIF-1α P402 or P564, suggesting regulation by PHD2 and not PHD3. Culturing villous explants under varying oxygen tensions revealed that E-PE, but not L-PE, placentae were unable to regulate HIF-1α levels because PHD2, FIH and SIAHs did not sense a hypoxic environment.


CONCLUSIONS
Disruption of oxygen sensing in E-PE vs. L-PE and control placentae is the first molecular evidence of the existence of two distinct preeclamptic diseases and the unique molecular O(2)-sensing signature of E-PE placentae may be of diagnostic value when assessing high risk pregnancies and their severity.
Rolfo
Alessandro
A
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Many
Ariel
A
Racano
Antonella
A
Tal
Reshef
R
Tagliaferro
Andrea
A
Ietta
Francesca
F
Wang
Jinxia
J
Post
Martin
M
Caniggia
Isabella
I
D000328:Adult; D001483:Base Sequence; D015153:Blotting, Western; D002460:Cell Line; D017931:DNA Primers; D005260:Female; D020868:Gene Silencing; D006801:Humans; D017403:In Situ Hybridization; D010100:Oxygen / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D034741:RNA, Small Interfering; D010100:Oxygen