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Redox regulation of SERCA2 is required for VEGF-induced signaling and endothelial cell migration.
MedLine Citation:
PMID:  22472004     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Aims: 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 is to define the role of ∙NO-mediated redox regulation of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) in VEGF-induced signaling and EC migration. Results: VEGF-induced EC migration was prevented by the ∙NO synthase inhibitor, LNAME. Either VEGF or ∙NO stimulated endoplasmic reticulum 45Ca2+ uptake, a measure of SERCA activity, and knockdown of SERCA2 prevented VEGF-induced EC migration and 45Ca2+ 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 EC overexpressing Glrx-1. VEGF or ∙NO increased SERCA S-glutathiolation and stimulated migration of EC 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 Ca2+ 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 and Ca2+ entry through Orai1 were also required for VEGF- and ∙NO induced EC Ca2+ 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 Ca2+ 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     Date:  2012-4-3
Journal Detail:
Title:  Antioxidants & redox signaling     Volume:  -     ISSN:  1557-7716     ISO Abbreviation:  -     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-4-4     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100888899     Medline TA:  Antioxid Redox Signal     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Boston University, Medicine, Boston, Massachusetts, United States; aliciae@bu.edu.
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