期刊
CIRCULATION RESEARCH
卷 108, 期 10, 页码 1190-U131出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.111.243352
关键词
endothelium; angiogenesis; calcium channels; growth factors
资金
- British Heart Foundation
- Wellcome Trust
- Medical Research Council
- BBSRC-AstraZeneca
- Egyptian Ministry of Higher Education
- University of Leeds
- China Scholarship Council
- BBSRC [BB/D524875/1] Funding Source: UKRI
- MRC [G0901761] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/D524875/1] Funding Source: researchfish
- Medical Research Council [G0901761] Funding Source: researchfish
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. (Circ Res. 2011;108:1190-1198.)
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