The CXCL12/CXCR4 Axis Plays a Critical Role in Coronary Artery Development

Summary

The chemokine CXCL12 and its receptor CXCR4 have many functions during embryonic and post-natal life. We used murine models to investigate the role of CXCL12/CXCR4 signaling in cardiac development and found that embryonic Cxcl12-null hearts lacked intra-ventricular coronary arteries (CAs) and exhibited absent or misplaced CA stems. We traced the origin of this phenotype to defects in the early stages of CA stem formation. CA stems derive from the peritruncal plexus, an encircling capillary network that invades the wall of the developing aorta. We showed that CXCL12 is present at high levels in the outflow tract, while peritruncal endothelial cells (ECs) express CXCR4. In the absence of CXCL12, ECs were abnormally localized and impaired in their ability to anastomose with the aortic lumen. We propose that CXCL12 is required for connection of peritruncal plexus ECs to the aortic endothelium and thus plays a vital role in CA formation.

Graphical Abstract

Highlights

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  Cxcl12 and Cxcr4 mutants lack intra-ventricular coronary arteries

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  Coronary artery stem formation is impaired in Cxcl12 mutants

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  Peritruncal blood vessels fail to penetrate the aortic endothelium

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  CXCL12 signaling is required for anastomosis of peritruncal endothelial cells

Abstract

Coronary artery stem formation depends on the establishment of connections between the peritruncal capillary network and the lumen of the developing aorta. Ivins et al. have shown that in mice deficient for the chemokine CXCL12, the formation of such connections is disrupted, leading to severe coronary artery defects.