Imperial College London
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DrAndrewCowburn

Faculty of Medicine, National Heart & Lung Institute

Senior Lecturer (Non-Clinical)
 
 
 
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Contact

 

a.cowburn

 
 
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Location

 

535ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Cowburn:2016:10.1073/pnas.1602978113,
author = {Cowburn, AS and Crosby, A and Macias, D and Branco, C and Colaco, RDDR and Southwood, M and Toshner, M and Alexander, LEC and Morrell, NW and Chilvers, ER and Johnson, RS},
doi = {10.1073/pnas.1602978113},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
pages = {8801--8806},
title = {HIF2 alpha-arginase axis is essential for the development of pulmonary hypertension},
url = {http://dx.doi.org/10.1073/pnas.1602978113},
volume = {113},
year = {2016}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Hypoxic pulmonary vasoconstriction is correlated with pulmonary vascular remodeling. The hypoxia-inducible transcription factors (HIFs) HIF-1α and HIF-2α are known to contribute to the process of hypoxic pulmonary vascular remodeling; however, the specific role of pulmonary endothelial HIF expression in this process, and in the physiological process of vasoconstriction in response to hypoxia, remains unclear. Here we show that pulmonary endothelial HIF-2α is a critical regulator of hypoxia-induced pulmonary arterial hypertension. The rise in right ventricular systolic pressure (RVSP) normally observed following chronic hypoxic exposure was absent in mice with pulmonary endothelial HIF-2α deletion. The RVSP of mice lacking HIF-2α in pulmonary endothelium after exposure to hypoxia was not significantly different from normoxic WT mice and much lower than the RVSP values seen in WT littermate controls and mice with pulmonary endothelial deletion of HIF-1α exposed to hypoxia. Endothelial HIF-2α deletion also protected mice from hypoxia remodeling. Pulmonary endothelial deletion of arginase-1, a downstream target of HIF-2α, likewise attenuated many of the pathophysiological symptoms associated with hypoxic pulmonary hypertension. We propose a mechanism whereby chronic hypoxia enhances HIF-2α stability, which causes increased arginase expression and dysregulates normal vascular NO homeostasis. These data offer new insight into the role of pulmonary endothelial HIF-2α in regulating the pulmonary vascular response to hypoxia.
AU  - Cowburn,AS
AU  - Crosby,A
AU  - Macias,D
AU  - Branco,C
AU  - Colaco,RDDR
AU  - Southwood,M
AU  - Toshner,M
AU  - Alexander,LEC
AU  - Morrell,NW
AU  - Chilvers,ER
AU  - Johnson,RS
DO  - 10.1073/pnas.1602978113
EP  - 8806
PY  - 2016///
SN  - 0027-8424
SP  - 8801
TI  - HIF2 alpha-arginase axis is essential for the development of pulmonary hypertension
T2  - Proceedings of the National Academy of Sciences of the United States of America
UR  - http://dx.doi.org/10.1073/pnas.1602978113
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000380586600068&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - http://hdl.handle.net/10044/1/64509
VL  - 113
ER  -
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