Document Detail

Homeostatic and tissue reparation defaults in mice carrying selective genetic invalidation of CXCL12/proteoglycan interactions.
MedLine Citation:
PMID:  23035208     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Interaction with heparan sulfate proteoglycans is supposed to provide chemokines with the capacity to immobilize on cell surface and extracellular matrix for accomplishing both tissue homing and signaling of attracted cells. However, the consequences of the exclusive invalidation of such interaction on the roles played by endogenous chemokines in vivo remain unascertained.
METHODS AND RESULTS: We engineered a mouse carrying a Cxcl12 gene (Cxcl12(Gagtm)) mutation that precludes interactions with heparan sulfate structures while not affecting CXCR4-dependent cell signaling of CXCL12 isoforms (α, β, γ). Cxcl12(Gagtm/Gagtm) mice develop normally, express normal levels of total and isoform-specific Cxcl12 mRNA, and show increased counting of circulating CD34(+) hematopoietic precursor cells. After induced acute ischemia, a marked impaired capacity to support revascularization was observed in Cxcl12(Gagtm/Gagtm) animals associated with a reduced number of infiltrating cells in the ischemic tissue despite the massive expression of CXCL12 isoforms. Importantly, exogenous administration of CXCL12γ, which binds heparan sulfate with the highest affinity ever reported for a cytokine, fully restores vascular growth, whereas heparan sulfate-binding CXCL12γ mutants failed to promote revascularization in Cxcl12(Gagtm/Gagtm) animals.
CONCLUSION: These findings prove the role played by heparan sulfate interactions in the functions of CXCL12 in both homeostasis and physiopathological settings and document for the first time the paradigm of chemokine immobilization in vivo.
Patricia Rueda; Adèle Richart; Alice Récalde; Pamela Gasse; José Vilar; Coralie Guérin; Hugues Lortat-Jacob; Paulo Vieira; Franoise Baleux; Fabrice Chretien; Fernando Arenzana-Seisdedos; Jean-Sébastien Silvestre
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-10-03
Journal Detail:
Title:  Circulation     Volume:  126     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-10-09     Completed Date:  2012-12-17     Revised Date:  2014-03-09    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1882-95     Citation Subset:  AIM; IM    
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MeSH Terms
Chemokine CXCL12 / biosynthesis,  genetics*
Heparin / analogs & derivatives*,  metabolism
Hindlimb / blood supply
Ischemia / genetics*,  metabolism
Models, Animal
Muscle, Skeletal / blood supply*
Neovascularization, Physiologic / genetics*
Protein Isoforms / genetics
Proteoglycans / metabolism*
RNA, Messenger
Transcription, Genetic
Reg. No./Substance:
0/Chemokine CXCL12; 0/Cxcl12 protein, mouse; 0/Protein Isoforms; 0/Proteoglycans; 0/RNA, Messenger; 0/heparin proteoglycan; 9005-49-6/Heparin

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

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