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

Abstract

SummaryThe 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.

DACH1 stimulates shear stress-guided endothelial cell migration and coronary artery growth through the CXCL12–CXCR4 signaling axis

“…This is also the case in the coronary vasculature. Here, the ligand is highly expressed around the outflow tract, where it attracts coronary plexus cells to the aorta to form the coronary artery stem (Ivins et al 2015). We show that arterial endothelial cells in the heart also express Cxcl12 in a Dach1-dependent manner and propose that CXCL12 is part of the signal stimulating endothelial cells to migrate against flow into developing arteries.…”

“…CXCL12 induces coronary endothelial cell migration onto the heart in zebrafish (Harrison et al 2015). In mice, it was shown to be expressed around the aorta, where it is important for mediating anastomosis of plexus endothelial cells with the aortic lumen (Cavallero et al 2015;Ivins et al 2015). These reports also found Cxcl12 and Cxcr4 in large intramyocardial blood vessels; however, a potential role of coronary artery-derived CXCL12 was not explored.…”

“…Studies of the avian and mammalian yolk sac have shown that blood flow is required for plexus remodeling (Lucitti et al 2007). Arterial remodeling in the heart's coronary plexus directly follows initiation of blood flow and does not occur in mutants where the coronary artery does not connect to its blood flow source, the aorta (Chen et al 2014a;Ivins et al 2015;Volz et al 2015). Live imaging of the yolk sac and regenerating zebrafish fins revealed that arterial remodeling involves vessel fusion and endothelial migration against blood flow, toward the growing artery (Sato et al 2010;Udan et al 2013;Xu et al 2014).…”

Endocardium Minimally Contributes to Coronary Endothelium in the Embryonic Ventricular Free Walls

“…Many studies and reviews in the past years have made valuable contributions to the ongoing debate on the origins of coronary vessels in the developing heart. [5][6][7][8]14,[23][24][25][26][27] A consensus has emerged that there are 3 important sources for coronary vessels: proepicardium, VE, and SV. [1][2][3][4]28 Each source represents a unique developmental origin that may determine different models of coronary vessels formation.…”

Analysis of Coronary Vessels in Cleared Embryonic Hearts

“…Vessels that develop within the ventricular myocardium will go on to form the capillary and arterial networks delivering oxygenated blood to the heart tissue 18 . At the same time (around E11.5) the coronary stems begin to develop independently from a separate capillary network (known as the peritruncal plexus) that surrounds the lumen of the aorta 14,19,20 . Peritruncal plexus ECs initially form multiple connections with the lumen of the aorta at the level of the valve sinuses, however ultimately only one vessel will persist on each side of the aorta, going on to form the roots of the left and right coronary arteries 21 .…”