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Regulation of Cardiovascular Development and Physiology by Hypoxia-Inducible Factor 1a

Authors

  • GREGG L. SEMENZA,

    Corresponding author
    1. Institute of Genetic Medicine and Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
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  • FATON AGANI,

    1. Institute of Genetic Medicine and Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
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  • NARAYAN IYER,

    1. Institute of Genetic Medicine and Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
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  • LORI KOTCH,

    1. Institute of Genetic Medicine and Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
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  • ERIK LAUGHNER,

    1. Institute of Genetic Medicine and Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
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  • SANDRA LEUNG,

    1. Institute of Genetic Medicine and Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
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  • AIMEE YU

    1. Institute of Genetic Medicine and Departments of Pediatrics and Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA
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  • a

    This work was supported by grants from the American Heart Association National Center and the National Institutes of Health (ROI-DK39869 and ROI-HL55338). G.L.S. is an Established Investigator of the American Heart Association.

Address correspondence to: Gregg L. Semenza, M.D., Ph.D., Johns Hopkins Hospital, CMSC-1004, 600 North Wolfe Street, Baltimore, MD 21287-3914; Telephone: 410-955-1619; Fax: 410-955-0484; E-mail: gsemenza@jhmi.edu

Abstract

Abstract: Hypoxia is an essential pathophysiologic component of ischemic cardiovascular disease. A better understanding of the molecular mechanisms underlying adaptive responses to hypoxia may lead to novel therapeutic strategies. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic-helix-loop-helix-PAS domain transcription factor that mediates changes in gene expression in response to changes in O2 concentration. Genes that are transcriptionally activated by HIF-1 in hypoxic cells encode proteins that increase O2 delivery or allow metabolic adaptation to limited O2 availability. HIF-1 target genes include those encoding vascular endothelial growth factor (VEGF), erythropoietin, glucose transporters, and glycolytic enzymes. In anemic fetal sheep, increased myocardial vascularization was associated with concomitant increases in the expression of HIF-1 and VEGF. Expression of HIF-1 target genes was not induced by hypoxia in embryonic stem cells lacking expression of the O2-regulated HIF-1αa subunit. Mouse embryos lacking HIF-1α expression arrested in their development by E9.0 and died by E10.5 with cardiovascular malformations and massive cell death throughout the embryo. These studies indicate that HIF-1 functions as a master regulator of O2 homeostasis that controls the establishment of essential physiologic systems during embryogenesis as well as their subsequent utilization during fetal and postnatal life.

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