Human placental hypoxia-inducible factor-1α expression correlates with clinical outcomes in chronic hypoxia in vivo

被引:87
|
作者
Zamudio, Stacy
Wu, Yuanhong
Ietta, Francesca
Rolfo, Alessandro
Cross, Ashley
Wheeler, Timothy
Post, Martin
Illsley, Nicholas P.
Caniggia, Isabella
机构
[1] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Obstet Gynecol & Womens Hlth, Newark, NJ 07103 USA
[2] Mt Sinai Hosp, Dept Obstet & Gynecol, Toronto, ON M5G 1X5, Canada
[3] Univ Southampton, Sch Med, Div Dev Origins Hlth & Dis, Southampton, Hants, England
[4] Univ Toronto, Hosp Sick Children, Dept Pediat, Toronto, ON M5G 1X8, Canada
[5] Univ Toronto, Dept Physiol, Toronto, ON M5G 1X8, Canada
来源
AMERICAN JOURNAL OF PATHOLOGY | 2007年 / 170卷 / 06期
关键词
D O I
10.2353/ajpath.2007.061185
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
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 RA by increasing erythropoiesis and placental angiogenesis. We therefore investigated HIF expression and its regulatory mechanisms in placentas from normal pregnancies at high (3100 in), moderate (1600 in), and sea level (75 in) altitudes. Moderate-altitude and sea level placentas did not differ, but HrF-1 alpha and the von Hippel-Lindau tumor suppressor protein were overexpressed in RA placentas. The ability of von Hippel-Lindau tumor suppressor protein to form the E3 ubiquitin protein ligase complex, required for HIF-1 alpha degradation, was unaltered in RA placentas. mRNA for factor-inhibiting HIF, a negative modulator of HIF-1 alpha transactivation, was increased, but protein levels were diminished. Elevated HIF-1 alpha likely contributed to the significant increase we report in HIF-1 alpha downstream target proteins, transforming growth factor 63 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-1 alpha, 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.
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收藏
页码:2171 / 2179
页数:9
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