Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 43, Pages 17570-17575Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1306942110
Keywords
HIF-alpha; arginase; vascular tone
Categories
Funding
- Cambridge National Institute for Health Research Biomedical Research Center
- Papworth Hospital National Health Service trust
- Wellcome Trust [WT092738MA]
- US National Institutes of Health [5R01AI093451, 1R01AI096852, 5R01CA153983]
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Vascular flow through tissues is regulated via a number of homeostatic mechanisms. Localized control of tissue blood flow, or autoregulation, is a key factor in regulating tissue perfusion and oxygenation. We show here that the net balance between two hypoxia-inducible factor (HIF) transcription factor isoforms, HIF-1 alpha and HIF-2 alpha, is an essential mechanism regulating both local and systemic blood flow in the skin of mice. We also show that balance of HIF isoforms in keratinocyte-specific mutant mice affects thermal adaptation, exercise capacity, and systemic arterial pressure. The two primary HIF isoforms achieve these effects in opposing ways that are associated with HIF isoform regulation of nitric oxide production. We also show that a correlation exists between altered levels of HIF isoforms in the skin and the degree of idiopathic hypertension in human subjects. Thus, the balance between HIF-1 alpha and HIF-2 alpha expression in keratinocytes is a control element of both tissue perfusion and systemic arterial pressure, with potential implications in human hypertension.
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