HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 75/1/112    most recent biolreprod.106.051557v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed 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 Ietta, F. Articles by Caniggia, I. Search for Related Content PubMed PubMed Citation Articles by Ietta, F. Articles by Caniggia, I. Agricola Articles by Ietta, F. Articles by Caniggia, I.

Dynamic HIF1A Regulation During Human Placental Development¹

Department of Obstetrics and Gynecology,³ Mount Sinai Hospital, Department of Pediatrics,⁴ The Hospital for Sick Children, Department of Physiology,⁵ University of Toronto, Toronto, Ontario, Canada M5G 1X5

ABSTRACT

The human placenta is a unique organ in terms of oxygenation as it undergoes a transition from a low to a more oxygenated environment. This physiological switch in oxygen tension is a prerequisite for proper placental development and involves the hypoxia inducible factor (HIF). HIF is stable and initiates gene transcription under hypoxia, whereas in normoxia, interaction with the von Hippel-Lindau tumor suppressor protein (VHL) leads to rapid degradation of the HIF1A subunit. The degradation requires formation of a multiprotein complex (VHL^CBC) and hydroxylation of HIF1A proline residues via members of the egg-laying-defective nine (EGLN) family. Herein, we have investigated the regulatory mechanisms of HIF1A expression during human placental development. Expression of HIF1A and VHL was high at 7–9 wk of gestation, when oxygen tension is low, and decreased when placental oxygen tension increases (10–12 wk of gestation). During early placentation, HIF1A localized in cytotrophoblasts, while VHL was present in syncytiotrophoblasts. At 10–12 wk, VHL appeared in cytotrophoblast cells, which coincided with the disappearance of HIF1A. At the same time the association of VHL and Cullin 2 as well as ubiquitination of HIF1A was maximal. EGLN1, EGLN2, and EGLN3 were also temporally expressed in an oxygen-dependent fashion, with greatest mRNA expression at 10–12 wk of gestation. Inhibition of EGLN activity increased HIF1A stability in villous explants and stimulated transforming growth factor beta 3 (TGFB3) expression consistent with promoter analyses showing that HIF1A transactivates TGFB3. These data demonstrate that during placental development, HIF1A is regulated by temporal and spatial changes in expression and association of molecules forming the multi-protein VHL^CBC complex as well as prolyl hydroxylase activities.

gene regulation, placenta, trophoblast

¹ Supported by Canadian Institutes of Health Research (CIHR) grant MT1406 to I.C.

² Correspondence: Isabella Caniggia, Mount Sinai Hospital, Samuel Lunenfeld Research Institute, 600 University Ave., Room 871, Toronto, ON, Canada M5G 1X5. FAX: 416 586 8588; caniggia{at}mshri.on.ca

This article has been cited by other articles:

				Y. Yinon, O. Nevo, J. Xu, A. Many, A. Rolfo, T. Todros, M. Post, and I. Caniggia Severe Intrauterine Growth Restriction Pregnancies Have Increased Placental Endoglin Levels: Hypoxic Regulation via Transforming Growth Factor- 3 Am. J. Pathol., January 1, 2008; 172(1): 77 - 85. [Abstract] [Full Text] [PDF]

				F. A. Groenman, M. Rutter, J. Wang, I. Caniggia, D. Tibboel, and M. Post Effect of chemical stabilizers of hypoxia-inducible factors on early lung development Am J Physiol Lung Cell Mol Physiol, September 1, 2007; 293(3): L557 - L567. [Abstract] [Full Text] [PDF]

				S. Zamudio, Y. Wu, F. Ietta, A. Rolfo, A. Cross, T. Wheeler, M. Post, N. P. Illsley, and I. Caniggia Human Placental Hypoxia-Inducible Factor-1{alpha} Expression Correlates with Clinical Outcomes in Chronic Hypoxia in Vivo Am. J. Pathol., June 1, 2007; 170(6): 2171 - 2179. [Abstract] [Full Text] [PDF]

				F. Groenman, M. Rutter, I. Caniggia, D. Tibboel, and M. Post Hypoxia-inducible Factors in the First Trimester Human Lung J. Histochem. Cytochem., April 1, 2007; 55(4): 355 - 363. [Abstract] [Full Text] [PDF]

				F. Ietta, Y. Wu, R. Romagnoli, N. Soleymanlou, B. Orsini, S. Zamudio, L. Paulesu, and I. Caniggia Oxygen regulation of macrophage migration inhibitory factor in human placenta Am J Physiol Endocrinol Metab, January 1, 2007; 292(1): E272 - E280. [Abstract] [Full Text] [PDF]