Selective overexpression of the hypoxia-inducible transcription factor, HIF-2alpha, in placentas from women with preeclampsia.

Transcription factors orchestrate the development of extraembryonic tissues. Because placental hypoxia likely plays an important role in both normal and abnormal placentation, we have been investigating the hypoxia-inducible transcription factors (HIFs) in the human placenta. In this report, we focus on the placentas from women with preeclampsia. Because the placenta is a large, heterogeneous organ, we employed a systematic and unbiased approach to placental sampling, and our results are based on the analyses of eight biopsy sites per placenta. We observed no significant differences in HIF-1alpha or -2alpha mRNA expression between normal term and preeclamptic placentas. Nor was HIF protein expression significantly different, with the notable exception of HIF-2alpha, which, on average, was increased by 1.7-fold in the preeclamptic placentas (P: < 0.03 vs. normal term placentas). Considering all 48 paired placental biopsy sites (eight sites each for six normal term and six preeclamptic placentas), HIF-2alpha protein levels in the preeclamptic placentas exceeded those in the normal term placentas in 39, or 81%, of the paired sites (P: < 0.0013). The HIF-2alpha immunoreactivity was mainly located in the nuclei of the syncytiotrophoblast and fetoplacental vascular endothelium in the preeclamptic villous placenta. To control for the earlier gestational age of the preeclamptic placentas, an additional group of placentas from preterm deliveries without preeclampsia were also evaluated. The HIF protein expression was comparable in these preterm specimens and the normal term placentas. We conclude that protein expression of HIF-2alpha, but not of HIF-1alpha or -1beta, is selectively increased in the preeclamptic placenta. The molecular mechanism(s) of this abnormality as well as the genes affected downstream are currently under investigation. To our knowledge, this is the first report of abnormal HIF-2alpha expression in human disease other than cancer.

Dietary supplementation with arachidonic and docosahexaenoic acids has no effect on pulmonary surfactant in artificially reared infant rats.

Despite the potential use of long chain polyunsaturated fatty acid (LCPUFA) supplementation to promote growth and neural development of the infant, little is known about potential harmful effects of the supplementation. The present study determined whether supplementation with arachidonic acid (AA) and/or docosahexaenoic acid (DHA) in rat milk formula (RMF) affects saturation of pulmonary surfactant phospholipids (PL). Beginning at 7 d of age, infant rats were artificially fed for 10 d with RMF supplemented with AA at 0, 0.5, and 1.0% of total fatty acid, or supplemented with DHA at 0, 0.5, and 1.0%, or cosupplemented with AA and DHA at levels of 0:0, 0.5:0.3, and 1.0:0.6% of the fat blend. Lung tissue PL contained 43 weight percent palmitate (16:0) of total fatty acids in infant rats fed the unsupplemented RMF. The supplementation with AA at both 0.5 and 1.0% decreased the weight percentage of 16:0 and stearate (18:0), indicating a decrease in saturation of PL. The observed decreases were accompanied by increases in AA and linoleic acid (18:2n-6). Surfactant phosphatidylcholine (PC) consisted of 71 weight percent 16:0 in the unsupplemented group, and this highly saturated PC was not altered by the cosupplementation with AA and DHA although there was a slight increase in DHA. Similarly, the cosupplementation did not change fatty acid composition of surfactant PL when compared with the unsupplemented group. The cosupplementation slightly decreased the weight percentage of 16:0 with a proportional increase in 18:0 leading to an unchanged weight percentage of total saturated fatty acids. These results suggest that, unlike lung tissue PL, the composition of saturated fatty acids in surfactant PL, particularly PC, is resistant to change by dietary AA and DHA supplementation. This, together with the unchanged concentration of total fatty acids in surfactant PC, indicates that LCPUFA cosupplementation causes no effect on pulmonary surfactant.