Published online before print April 19, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: ajpath.2007.061185v1 170/6/2171    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zamudio, S. Articles by Caniggia, I. Search for Related Content PubMed Articles by Zamudio, S. Articles by Caniggia, I.

(American Journal of Pathology. 2007;170:2171-2179.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.061185

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

Stacy Zamudio^*, Yuanhong Wu, Francesca Ietta, Alessandro Rolfo, Ashley Cross, Timothy Wheeler, Martin Post^¶, Nicholas P. Illsley^* and Isabella Caniggia^¶

From the Department of Obstetrics,^* Gynecology and Women’s Health, New Jersey Medical School, Newark, New Jersey; the Department of Obstetrics and Gynecology, Mount Sinai Hospital, Toronto, Ontario, Canada; the School of Medicine, Division of Developmental Origins of Health and Disease, University of Southampton, Southampton, United Kingdom; and the Department of Pediatrics, The Hospital for Sick Children, and the Department of Physiology,^¶ University of Toronto, Toronto, Ontario, Canada

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-1 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-1 degradation, was unaltered in HA placentas. mRNA for factor-inhibiting HIF, a negative modulator of HIF-1 transactivation, was increased, but protein levels were diminished. Elevated HIF-1 likely contributed to the significant increase we report in HIF-1 downstream target proteins, transforming growth factor ß3 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, 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.

This article has been cited by other articles:

				K.G. Pringle, K.L. Kind, A.N. Sferruzzi-Perri, J.G. Thompson, and C.T. Roberts Beyond oxygen: complex regulation and activity of hypoxia inducible factors in pregnancy Hum. Reprod. Update, November 19, 2009; (2009) dmp046v1. [Abstract] [Full Text] [PDF]

				L. Postigo, G. Heredia, N. P. Illsley, T. Torricos, C. Dolan, L. Echalar, W. Tellez, I. Maldonado, M. Brimacombe, E. Balanza, et al. Where the O2 goes to: preservation of human fetal oxygen delivery and consumption at high altitude J. Physiol., February 1, 2009; 587(3): 693 - 708. [Abstract] [Full Text] [PDF]

				R. Trollmann, K. Strasser, S. Keller, X. Antoniou, B. Grenacher, O. O. Ogunshola, J. Dotsch, W. Rascher, and M. Gassmann Placental HIFs as markers of cerebral hypoxic distress in fetal mice Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2008; 295(6): R1973 - R1981. [Abstract] [Full Text] [PDF]