Document Detail


Redox regulation of SERCA2 is required for vascular endothelial growth factor-induced signaling and endothelial cell migration.
MedLine Citation:
PMID:  22472004     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
AIMS: Vascular endothelial growth factor (VEGF) increases angiogenesis by stimulating endothelial cell (EC) migration. VEGF-induced nitric oxide ((•)NO) release from (•)NO synthase plays a critical role, but the proteins and signaling pathways that may be redox-regulated are poorly understood. The aim of this work was to define the role of (•)NO-mediated redox regulation of the sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA) in VEGF-induced signaling and EC migration.
RESULTS: VEGF-induced EC migration was prevented by the (•)NO synthase inhibitor, N (G)-nitro-L-arginine methyl ester (LNAME). Either VEGF or (•)NO stimulated endoplasmic reticulum (ER) (45)Ca(2+) uptake, a measure of SERCA activity, and knockdown of SERCA2 prevented VEGF-induced EC migration and (45)Ca(2+) uptake. S-glutathione adducts on SERCA2b, identified immunochemically, were increased by VEGF, and were prevented by LNAME or overexpression of glutaredoxin-1 (Glrx-1). Furthermore, VEGF failed to stimulate migration of ECs overexpressing Glrx-1. VEGF or (•)NO increased SERCA S-glutathiolation and stimulated migration of ECs in which wild-type (WT) SERCA2b was overexpressed with an adenovirus, but did neither in those overexpressing a C674S SERCA2b mutant, in which the reactive cysteine-674 was mutated to a serine. Increased EC Ca(2+) influx caused by VEGF or (•)NO was abrogated by overexpression of Glrx-1 or the C674S SERCA2b mutant. ER store-emptying through the ryanodine receptor (RyR) and Ca(2+) entry through Orai1 were also required for VEGF- and (•)NO-induced EC Ca(2+) influx.
INNOVATION AND CONCLUSIONS: These results demonstrate that (•)NO-mediated activation of SERCA2b via S-glutathiolation of cysteine-674 is required for VEGF-induced EC Ca(2+) influx and migration, and establish redox regulation of SERCA2b as a key component in angiogenic signaling.
Authors:
Alicia M Evangelista; Melissa D Thompson; Robert M Weisbrod; David R Pimental; Xiaoyong Tong; Victoria M Bolotina; Richard A Cohen
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-05-31
Journal Detail:
Title:  Antioxidants & redox signaling     Volume:  17     ISSN:  1557-7716     ISO Abbreviation:  Antioxid. Redox Signal.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-08-22     Completed Date:  2014-01-30     Revised Date:  2014-11-13    
Medline Journal Info:
Nlm Unique ID:  100888899     Medline TA:  Antioxid Redox Signal     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1099-108     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adult
Calcium / metabolism
Cell Movement*
Endothelial Cells / cytology*,  metabolism*
Female
Humans
Nitric Oxide / metabolism
Oxidation-Reduction
Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics,  metabolism*
Signal Transduction*
Vascular Endothelial Growth Factor A / metabolism*
Young Adult
Grant Support
ID/Acronym/Agency:
HL007501-26/HL/NHLBI NIH HHS; HL031607-29/HL/NHLBI NIH HHS; R01 HL054150/HL/NHLBI NIH HHS; R01 HL071793/HL/NHLBI NIH HHS; R01-HL071793/HL/NHLBI NIH HHS; R01-HL54150/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Vascular Endothelial Growth Factor A; 31C4KY9ESH/Nitric Oxide; EC 3.6.3.8/ATP2A2 protein, human; EC 3.6.3.8/Sarcoplasmic Reticulum Calcium-Transporting ATPases; SY7Q814VUP/Calcium
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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