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HIF isoforms in the skin differentially regulate systemic arterial pressure.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Cowburn, Andrew S 
Takeda, Norihiko 
Boutin, Adam T 
Kim, Jung-Whan 
Sterling, Jane C 

Abstract

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-1α and HIF-2α, 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-1α and HIF-2α expression in keratinocytes is a control element of both tissue perfusion and systemic arterial pressure, with potential implications in human hypertension.

Description

Keywords

HIF-alpha, arginase, vascular tone, Adult, Aged, Animals, Arginase, Arterial Pressure, Basic Helix-Loop-Helix Transcription Factors, Blotting, Western, Female, Humans, Hypertension, Hypoxia-Inducible Factor 1, alpha Subunit, Immunohistochemistry, Keratinocytes, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Nitric Oxide Synthase Type II, Nitric Oxide Synthase Type III, Regional Blood Flow, Reverse Transcriptase Polymerase Chain Reaction, Skin, Young Adult

Journal Title

Proc Natl Acad Sci U S A

Conference Name

Journal ISSN

0027-8424
1091-6490

Volume Title

110

Publisher

Proceedings of the National Academy of Sciences
Sponsorship
National Cancer Institute (R01CA153983)
Wellcome Trust (092738/Z/10/Z)
National Institute of Allergy and Infectious Diseases (R56AI090863)
National Institute of Allergy and Infectious Diseases (R01AI096852)
National Institute of Allergy and Infectious Diseases (R01AI093451)