HIF isoforms in the skin differentially regulate systemic arterial pressure

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-10, Vol.110 (43), p.17570-17575
• Main Authors: Cowburn, Andrew S., Takeda, Norihiko, Boutin, Adam T., Kim, Jung-Whan, Sterling, Jane C., Nakasaki, Manando, Southwood, Mark, Goldrath, Ananda W., Jamora, Colin, Nizet, Victor, Chilvers, Edwin R., Johnson, Randall S.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Animals; Arginase - genetics; Arginase - metabolism; Arterial Pressure - physiology; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biological Sciences; Biopsies; Blood pressure; Blotting, Western; Correlation analysis; Female; Gene expression regulation; Homeostasis; Humans; Hypertension; Hypertension - drug therapy; Hypertension - physiopathology; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Immunohistochemistry; Keratinocytes; Keratinocytes - cytology; Keratinocytes - metabolism; Male; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Nitric oxide; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - metabolism; Nitric Oxide Synthase Type III - genetics; Nitric Oxide Synthase Type III - metabolism; Oxides; Protein isoforms; Regional Blood Flow - physiology; Reverse Transcriptase Polymerase Chain Reaction; Skin; Skin - blood supply; Skin - metabolism; Tissues; Young Adult
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1306942110

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.