Dysregulation of Oxygen Sensing/Response Pathways in Pregnancies Complicated by Idiopathic Intrauterine Growth Restriction and Early-Onset Preeclampsia

Abstract

Preeclampsia (PE) and intrauterine growth restriction (IUGR) are the leading causes of maternal and fetal morbidity/mortality. The central deficit in both conditions is impaired placentation due to poor trophoblast invasion, resulting in a hypoxic milieu in which oxidative stress contributes to the pathology. We examine the factors driving the hypoxic response in severely preterm PE (n = 19) and IUGR (n = 16) placentae compared to the spontaneous preterm (SPT) controls (n = 13) using immunoblotting, RT-PCR, immunohistochemistry, proximity ligation assays, and Co-IP. Both hypoxia-inducible factor (HIF)-1a and HIF-2a are increased at the protein level and functional in pathological placentae, as target genes prolyl hydroxylase domain (PHD)2, PHD3, and soluble fms-like tyrosine kinase-1 (sFlt-1) are increased. Accumulation of HIF-a-subunits occurs in the presence of accessory molecules required for their degradation (PHD1, PHD2, and PHD3 and the E3 ligase von Hippel–Lindau (VHL)), which were equally expressed or elevated in the placental lysates of PE and IUGR. However, complex formation between VHL and HIF-a-subunits is defective. This is associated with enhanced VHL/DJ1 complex formation in both PE and IUGR. In conclusion, we establish a significant mechanism driving the maladaptive responses to hypoxia in the placentae from severe PE and IUGR, which is central to the pathogenesis of both diseases.

Development and evaluation of a nomogram for adverse outcomes of preeclampsia in Chinese pregnant women

“…Placental dysplasia is the main cause of early-onset preeclampsia. The abnormal invasion of trophoblast cells caused many pathophysiological changes in the inner wall of uterus, such as vascular reorganization and shallow implantation, which led to high resistance of blood vessels, insufficient perfusion of multiple organs and involvement of uterine spiral arteries[ 40 ]. Because of the decrease of placental blood supply and the aggravation of placental villus hypoxia and ischemia, the intake of nutrients and oxygen by the fetus decreases, which had adverse effects on the growth and development of the fetus.…”

From Molecules to Imaging: Assessment of Placental Hypoxia Biomarkers in Placental Insufficiency Syndromes

“…This suggests that the levels of oxygen Overview of the molecular and imaging biomarkers of placental hypoxia. HIF-α [16][17][18][19][20][21][22][23][24][25]28,30,38], CAIX [13,42,43], miR-210 [14,[46][47][48][49][50], T2* MRI [16,55,56,59,[62][63][64], PAI [35,37,67].…”

“…Others also showed that HIF-1α expression is elevated in prenatal blood samples taken at the diagnosis of PE, as well as in postnatal blood samples from pregnancies affected by PE when compared to control samples [ 19 ]. After delivery, studies conducted on ex vivo placental tissue have consistently demonstrated elevated levels of HIF-1α and HIF-2α in pregnancies affected by PE and FGR [ 20 , 21 , 22 , 23 , 24 , 25 ]. Nevertheless, the number of studies simultaneously examining both HIF-1α and HIF-2α is limited, but the available research suggests that HIF-2α, rather than HIF-1α, is prominently induced in placentas from patients with FGR and PE [ 26 , 27 ].…”

“… Overview of the molecular and imaging biomarkers of placental hypoxia. HIF-α [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 28 , 30 , 38 ], CAIX [ 13 , 42 , 43 ], miR-210 [ 14 , 46 , 47 , 48 , 49 , 50 ], T2* MRI [ 16 , 55 , 56 , 59 , 62 , 63 , 64 ], PAI [ 35 , 37 , 67 ]. …”

Impact of Endogenic and Exogenic Oxidative Stress Triggers on Pregnant Woman, Fetus, and Child

“…McCracken SA et al [ 6 ] examined the factors driving the hypoxic response in severely preterm PE and IUGR placentae compared to the spontaneous preterm (SPT) controls using immunoblotting, RT-PCR, immunohistochemistry, proximity ligation assays, and Co-IP.…”