CXCL12 And Vascular Maturation Of The Coronary System During Heart Development
Authors: Cavallero Susana , Shen Hua , Yi Christopher , Subramanyan Ram Kumar , Sucov Henry 
Published: November 2023

Elucidating the mechanisms involved in the patterning of coronary blood vessels in the embryo will help to improve therapies for coronary perfusion in the injured heart. In the past few years, there have been significant efforts and advances in the understanding of coronary vessel development. The major endothelial cell sources that provide coronary endothelial progenitors to the heart are the sinus venosus (the vein that delivers the venous return) and the endocardium, although the respective contribution from each source is debated. Angiogenic sprouts from the sinus venosus reach the ventricles starting at E11.5 in the mouse and form a vascular plexus in the subepicardial space. This primitive plexus undergoes a complex and incompletely understood process of vascular maturation that involves pruning, branching and reorganization into a hierarchical network of superficial veins and intramyocardial arteries. The main branches of the coronary arteries ultimately connect to the aorta through the coronary ostia by E13.5 – E14.0.

CXCL12 (also known as stromal derived factor 1, SDF1) is a chemokine that acts through the G protein‐coupled receptor CXCR4. Global deficiency of Cxcl12 or Cxcr4 as well as endothelial deletion of Cxcr4 result in vascular defects in the mouse kidney and gut, but these defects do not explain the associated late gestation lethality. We hypothesized that coronary vascular defects might underlie the embryonic lethality of CXCL12 deficiency.

Cxcl12 and Tie2Cre/Cxcr4 mutants form an initial coronary vascular plexus, which then fails to remodel into a hierarchical network of mature vessels, resulting in the absence of the major intramyocardial coronary arteries, hemorrhage and reduced ventricular wall perfusion. The coronary veins were mostly unaffected, and the basis of the selectivity of CXCL12 on the arterial side of the vasculature is still unclear.

In vitro, CXCL12 does not induce sprouting of endothelial cells from beads embedded in a fibrin gel matrix, but instead promotes maturation of vascular sprouts preformed in response to VEGF, by increasing tube elongation, vessel branching, anastomosis and intussusception, all features of mature blood vessel networks. These features were abolished in the presence of AMD3100, a CXCR4 inhibitor. Thus, CXCL12 does not initiate vasculogenesis but rather promotes further remodeling of a plexus that is initially induced by VEGF.

We conclude that failed maturation of the coronary system explains the late‐gestation lethality of Cxcl12 mutants, and highlight the role of CXCL12 as an organ‐specific arterial maturation factor of particular relevance in the coronary vasculature. Our current studies are aimed at defining the role of CXCL12 in reprogramming of venous endothelial cells from the sinus venosus into coronary arterial endothelium.

Support or Funding Information

This work was supported by NIH grant HL070123 to H.M.S. and grant 14BGIA20500059 to S.R.K. from the American Heart Association. S.C. was supported by a Postdoctoral Fellowship from the American Heart Association. H.S. was supported by a Postdoctoral Fellowship from the California Institute for Regenerative Medicine.