HIF isoforms in the skin differentially regulate systemic arterial pressure

被引:68
作者
Cowburn, Andrew S. [1 ,2 ,4 ]
Takeda, Norihiko [4 ]
Boutin, Adam T. [4 ]
Kim, Jung-Whan [4 ]
Sterling, Jane C. [2 ]
Nakasaki, Manando [4 ]
Southwood, Mark [3 ]
Goldrath, Ananda W. [4 ]
Jamora, Colin [4 ]
Nizet, Victor [5 ]
Chilvers, Edwin R. [2 ]
Johnson, Randall S. [1 ]
机构
[1] Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge CB2 3EG, England
[2] Univ Cambridge, Dept Med, Cambridge CB2 3EG, England
[3] Natl Hlth Serv Fdn Trust, Papworth Hosp, Cambridge CB23 3RE, England
[4] Univ Calif San Diego, Dept Pediat, Div Biol Sci, La Jolla, CA 92093 USA
[5] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA
基金
英国惠康基金; 美国国家卫生研究院;
关键词
HIF-alpha; arginase; vascular tone; BLOOD-PRESSURE; L-ARGININE; HYPOXIA; OXYGEN; HYPERTENSION; HIF-2-ALPHA; MACROPHAGES; RESPONSES; ACTIVATION; MECHANISMS;
D O I
10.1073/pnas.1306942110
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:17570 / 17575
页数:6
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