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DEVELOPMENTAL PHYSIOLOGY AND PREGNANCY

Placental HIF-1, HIF-2, membrane and soluble VEGF receptor-1 proteins are not increased in normotensive pregnancies complicated by late-onset intrauterine growth restriction

Departments of ¹Obstetrics, Gynecology and Reproductive Sciences, and ²Epidemiology, Graduate School of Public Health and ⁴Cell Biology and Physiology, University of Pittsburgh School of Medicine and Magee Womens Research Institute Pittsburgh and ³Pediatrics, Allegheny General Hospital and Drexel University School of Medicine, Pittsburgh, Pennsylvania

Submitted 12 February 2007 ; accepted in final form 14 May 2007

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- (HIF-) 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 37 wk of gestation with birth weights of <10% and asymmetrical growth. HIF-1, -2, 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, -2, and Flt proteins were significantly increased by 50–100% (all P < 0.01 vs. 1.0). Unexpectedly, the IUGR/NP ratios for HIF-1 and -2 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- mRNA in abnormal and normal placentas. In contrast to PE, HIF- proteins and regulated genes are not increased in placentas from normotensive pregnant women delivering small, asymmetrically grown babies 37 wk of gestation. The absence of an increase in HIF- protein is not due to insufficient HIF- mRNA for protein synthesis. Thus, the placentas from women with PE and late IUGR are fundamentally different at the molecular level.

preeclampsia; fetal growth restriction; placenta; hypoxia-inducible transcription factors; Flt-1

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