Human Placental Hypoxia-Inducible Factor-1α Expression Correlates with Clinical Outcomes in Chronic Hypoxia in Vivo

Abstract

Placental hypoxia is causally implicated in fetal growth restriction and preeclampsia, with both occurring more frequently at high altitude (>2700 m; HA). The nuclear transcription factor hypoxia-inducible factor (HIF) may facilitate placental oxygen transport at HA by increasing erythropoiesis and placental angiogenesis. We therefore investigated HIF expression and its regulatory mechanisms in placentas from normal pregnancies at high (3100 m), moderate (1600 m), and sea level (75 m) altitudes. Moderate-altitude and sea level placentas did not differ, but HIF-1alpha and the von Hippel-Lindau tumor suppressor protein were overexpressed in HA placentas. The ability of von Hippel-Lindau tumor suppressor protein to form the E3 ubiquitin protein ligase complex, required for HIF-1alpha degradation, was unaltered in HA placentas. mRNA for factor-inhibiting HIF, a negative modulator of HIF-1alpha transactivation, was increased, but protein levels were diminished. Elevated HIF-1alpha likely contributed to the significant increase we report in HIF-1alpha downstream target proteins, transforming growth factor beta3 in the placenta, and vascular endothelial growth factor and erythropoietin in the maternal circulation. These circulating markers and lowered birth to placental weight ratios correlated with increased HIF-1alpha, thereby linking molecular and systemic physiological data. The HA response to chronic hypoxia resembles preeclampsia in several aspects, illustrating the utility of the HA model in understanding placental pathologies.

Effect of Black Seed (Nigella sativa) Ethanol Extract on The Expression of Hypoxia Inducible Factor-1a(HIF-1a) and Endothelial Nitric Oxide Synthase(eNOS) in Placenta of Preeclampsia Mice Model

“…The dominance of the brown color in the cells of placental tissue is particularly apparent fort rophoblast cells and also for endothelial cells from blood vessels in the placenta. This is consistent with previous studies showing that hypoxic conditions increased the expression of HIF-1α in the placenta in preeclampsia [9][10][11] . The decreased expression of eNOS in the placenta of mice with preeclampsia in this study was also proven by another research 8 .…”

Effect of Black Seed (Nigella sativa) Ethanol Extract on the Expression of Hypoxia Inducible Factor-1α(HIF-1α) and Endothelial Nitric Oxide Synthase(eNOS) in Placenta of Preeclampsia Mice Model

“…The dominance of the brown color in the cells of placental tissue is particularly apparent fortrophoblast cells and also for endothelial cells from blood vessels in the placenta. This is consistent with previous studies showing that hypoxic conditions increased the expression of HIF-1α in the placenta in preeclampsia [9][10][11] . The decreased expression of eNOSin the placenta of mice with preeclampsia in this study was also proven by another research 8 .…”

miR-210 Targets Iron-Sulfur Cluster Scaffold Homologue in Human Trophoblast Cell Lines

“…31 Preeclampsia and fetal growth restriction are more common in high-altitude regions. Zamudio et al 32 indicated that pregnancy at high altitude (3100 m) and chronic hypoxia in vivo are associated with an increased expression of HIF-1␣, resembling that of preeclampsia. Therefore, up-regulation of miR-210 in preeclamptic placentas seems to be biologically relevant, yet functional targets of miR-210 in the placenta have not been identified.…”