| Redox regulation of SERCA2 is required for VEGF-induced signaling and endothelial cell migration. | |
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MedLine Citation:
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PMID: 22472004 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: JOURNAL ARTICLE Date: 2012-4-3 |
Journal Detail:
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Title: Antioxidants & redox signaling Volume: - ISSN: 1557-7716 ISO Abbreviation: - Publication Date: 2012 Apr |
Date Detail:
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Created Date: 2012-4-4 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100888899 Medline TA: Antioxid Redox Signal Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Boston University, Medicine, Boston, Massachusetts, United States; aliciae@bu.edu. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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