Homeostatic and tissue reparation defaults in mice carrying selective genetic invalidation of CXCL12/proteoglycan interactions

Patricia Rueda, Adèle Richart, Alice Récalde, Pamela Gasse, José Vilar, Coralie Guérin, Hugues Lortat-Jacob, Paulo Vieira, Frano C. Baleux, Fabrice Chretien, Fernando Arenzana-Seisdedos, Jean Sébastien Silvestre

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37 Citations (Scopus)

Abstract

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) mutation that precludes interactions with heparan sulfate structures while not affecting CXCR4-dependent cell signaling of CXCL12 isoforms (α, β, γ). Cxcl12 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 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 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.

Original languageEnglish
Pages (from-to)1882-1895
Number of pages14
JournalCirculation
Volume126
Issue number15
DOIs
Publication statusPublished - 9 Oct 2012
Externally publishedYes

Keywords

  • angiogenesis-modulating agents
  • chemokine CXCL12
  • chemokines
  • ischemia
  • proteoglycans

Cite this

Rueda, P., Richart, A., Récalde, A., Gasse, P., Vilar, J., Guérin, C., Lortat-Jacob, H., Vieira, P., Baleux, F. C., Chretien, F., Arenzana-Seisdedos, F., & Silvestre, J. S. (2012). Homeostatic and tissue reparation defaults in mice carrying selective genetic invalidation of CXCL12/proteoglycan interactions. Circulation, 126(15), 1882-1895. https://doi.org/10.1161/CIRCULATIONAHA.112.113290