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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Orai1 and CRAC channel dependence of VEGF-activated Ca
2+
entry and endothelial tube formation
Circulation Research, Volume 108, No. 10, Year 2011
Notification
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Description
Rationale: Orai1 and the associated calcium release-activated calcium (CRAC) channel were discovered in the immune system. Existence also in endothelial cells has been suggested, but the relevance to endothelial biology is mostly unknown. Objective: The aim of this study was to investigate the relevance of Orai1 and CRAC channels to vascular endothelial growth factor (VEGF) and endothelial tube formation. Methods and Results: In human umbilical vein endothelial cells, Orai1 disruption by short-interfering RNA or dominant-negative mutant Orai1 inhibited calcium release-activated (store-operated) calcium entry, VEGF-evoked calcium entry, cell migration, and in vitro tube formation. Expression of exogenous wild-type Orai1 rescued the tube formation. VEGF receptor-2 and Orai1 partially colocalized. Orai1 disruption also inhibited calcium entry and tube formation in endothelial progenitor cells from human blood. A known blocker of the immune cell CRAC channel (3-fluoropyridine-4-carboxylic acid (2′,5′- dimethoxybiphenyl-4-yl)amide) was a strong blocker of store-operated calcium entry in endothelial cells and inhibited calcium entry evoked by VEGF in 3 types of human endothelial cell. The compound lacked effect on VEGF-evoked calcium-release, STIM1 clustering, and 2 types of transient receptor potential channels, TRPC6 and TRPV4. Without effect on cell viability, the compound inhibited human endothelial cell migration and tube formation in vitro and suppressed angiogenesis in vivo in the chick chorioallantoic membrane. The compound showed 100-fold greater potency for endothelial compared with immune cell calcium entry. Conclusions: The data suggest positive roles for Orai1 and CRAC channels in VEGF-evoked calcium entry and new opportunity for chemical modulation of angiogenesis. © 2011 American Heart Association, Inc.
Authors & Co-Authors
Li, Jing
United Kingdom, Leeds
Multidisciplinary Cardiovascular Research Centre
United Kingdom, Leeds
University of Leeds
Cubbon, Richard M.
United Kingdom, Leeds
Multidisciplinary Cardiovascular Research Centre
United Kingdom
Faculty of Medicine and Health
Wilson, Lesley A.
United Kingdom, Leeds
Multidisciplinary Cardiovascular Research Centre
United Kingdom, Leeds
University of Leeds
Amer, Mohamed S.
United Kingdom, Leeds
Multidisciplinary Cardiovascular Research Centre
United Kingdom, Leeds
University of Leeds
Egypt, Shibin el Kom
Menoufia University Faculty of Medicine
McKeown, Lynn
United Kingdom, Leeds
Multidisciplinary Cardiovascular Research Centre
United Kingdom, Leeds
University of Leeds
Hou, Bing
United Kingdom, Leeds
Multidisciplinary Cardiovascular Research Centre
United Kingdom, Leeds
University of Leeds
Majeed, Yasser
United Kingdom, Leeds
Multidisciplinary Cardiovascular Research Centre
United Kingdom, Leeds
University of Leeds
Tumova, Sarka
United Kingdom, Leeds
Multidisciplinary Cardiovascular Research Centre
United Kingdom, Leeds
University of Leeds
Seymour, Victoria A.L.
United Kingdom, Leeds
Multidisciplinary Cardiovascular Research Centre
United Kingdom, Leeds
University of Leeds
Taylor, Hilary
United Kingdom, Leeds
Multidisciplinary Cardiovascular Research Centre
United Kingdom, Leeds
University of Leeds
Stacey, Martin
United Kingdom, Leeds
Multidisciplinary Cardiovascular Research Centre
United Kingdom, Leeds
University of Leeds
O'Regan, David John
United Kingdom, Leeds
Leeds General Infirmary
Foster, Richard
United Kingdom, Leeds
University of Leeds
Porter, Karen E.
United Kingdom, Leeds
Multidisciplinary Cardiovascular Research Centre
United Kingdom
Faculty of Medicine and Health
Kearney, Mark T.
United Kingdom, Leeds
Multidisciplinary Cardiovascular Research Centre
United Kingdom
Faculty of Medicine and Health
Beech, David J.
United Kingdom, Leeds
Multidisciplinary Cardiovascular Research Centre
United Kingdom, Leeds
University of Leeds
Statistics
Citations: 178
Authors: 16
Affiliations: 5
Identifiers
Doi:
10.1161/CIRCRESAHA.111.243352
e-ISSN:
15244571
Research Areas
Cancer