title: Placental HIF-1 alpha, HIF-2 alpha, membrane and soluble VEGF receptor-1 proteins are not increased in normotensive pregnancies complicated by late-onset intrauterine growth restriction.
abstract: Inadequate trophoblast invasion and spiral artery remodeling leading to poor placental perfusion are believed to underlie the pregnancy pathologies preeclampsia (PE) and intrauterine growth restriction (IUGR). The main objective of this study was to investigate hypoxia-inducible transcription factor-alpha (HIF-alpha) and downstream genes (VEGF receptor-1) Flt-1 and soluble fms-like tyrosine kinase 1 (sFlt-1) proteins in IUGR placentas. Placentas from normal pregnant (NP; n = 18), PE (n = 18), and IUGR (n = 10) patients were investigated. Normotensive patients with IUGR delivered babies at >or= 37 wk of gestation with birth weights of <10% and asymmetrical growth. HIF-1 alpha, -2 alpha, Flt-1, and sFlt-1 protein, and mRNA were assessed by Western and Northern blot analyses, respectively. The results are expressed as ratios of the densitometric values for each pair of pathologic and normal placentas, a ratio of 1.0 indicating no difference. Comparable to our earlier studies, the PE/NP ratios for HIF-1 alpha, -2 alpha, and Flt proteins were significantly increased by 50-100% (all P < 0.01 vs. 1.0). Unexpectedly, the IUGR/NP ratios for HIF-1 alpha and -2 alpha proteins were 1.03 +/- 0.07 and 0.96 +/- 0.16, respectively, and for Flt and sFlt were 1.14 +/- 0.15 and 0.95 +/- 0.12, respectively (all P = not significant vs. 1.0). Northern blot analysis revealed comparable levels of HIF-alpha mRNA in abnormal and normal placentas. In contrast to PE, HIF-alpha proteins and regulated genes are not increased in placentas from normotensive pregnant women delivering small, asymmetrically grown babies >or= 37 wk of gestation. The absence of an increase in HIF-alpha protein is not due to insufficient HIF-alpha mRNA for protein synthesis. Thus, the placentas from women with PE and late IUGR are fundamentally different at the molecular level.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Graduate School of Public Health, University of Pittsburgh School of Medicine and Magee Womens Research Institute Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Augustine
authors.initials: A
authors.lastname: Rajakumar
authors.forename: Arun
authors.initials: A
authors.lastname: Jeyabalan
authors.forename: Nina
authors.initials: N
authors.lastname: Markovic
authors.forename: Roberta
authors.initials: R
authors.lastname: Ness
authors.forename: Carol
authors.initials: C
authors.lastname: Gilmour
authors.forename: Kirk P
authors.initials: KP
authors.lastname: Conrad
mesh_terms: D000328:Adult; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D001794:Blood Pressure; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D010920:Placenta / Q000502:physiology*; D011247:Pregnancy; D011263:Pregnancy Trimester, Third; D012333:RNA, Messenger / Q000378:metabolism; D012995:Solubility; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics* / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D012333:RNA, Messenger; D040281:Vascular Endothelial Growth Factor Receptor-1; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human