VEGF-C and aortic cardiomyocytes guide coronary artery stem development
Heidi I. Chen, … , Kari Alitalo, Kristy Red-Horse
Heidi I. Chen, … , Kari Alitalo, Kristy Red-Horse
Published October 1, 2014
Citation Information: J Clin Invest. 2014;124(11):4899-4914. https://doi.org/10.1172/JCI77483.
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Research Article Vascular biology

VEGF-C and aortic cardiomyocytes guide coronary artery stem development

Abstract

Coronary arteries (CAs) stem from the aorta at 2 highly stereotyped locations, deviations from which can cause myocardial ischemia and death. CA stems form during embryogenesis when peritruncal blood vessels encircle the cardiac outflow tract and invade the aorta, but the underlying patterning mechanisms are poorly understood. Here, using murine models, we demonstrated that VEGF-C–deficient hearts have severely hypoplastic peritruncal vessels, resulting in delayed and abnormally positioned CA stems. We observed that VEGF-C is widely expressed in the outflow tract, while cardiomyocytes develop specifically within the aorta at stem sites where they surround maturing CAs in both mouse and human hearts. Mice heterozygous for islet 1 (Isl1) exhibited decreased aortic cardiomyocytes and abnormally low CA stems. In hearts with outflow tract rotation defects, misplaced stems were associated with shifted aortic cardiomyocytes, and myocardium induced ectopic connections with the pulmonary artery in culture. These data support a model in which CA stem development first requires VEGF-C to stimulate vessel growth around the outflow tract. Then, aortic cardiomyocytes facilitate interactions between peritruncal vessels and the aorta. Derangement of either step can lead to mispatterned CA stems. Studying this niche for cardiomyocyte development, and its relationship with CAs, has the potential to identify methods for stimulating vascular regrowth as a treatment for cardiovascular disease.

Authors

Heidi I. Chen, Aruna Poduri, Harri Numi, Riikka Kivela, Pipsa Saharinen, Andrew S. McKay, Brian Raftrey, Jared Churko, Xueying Tian, Bin Zhou, Joseph C. Wu, Kari Alitalo, Kristy Red-Horse

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Figure 8

Ectopic vessel connections with the pulmonary artery lumen can form in the presence of cardiomyocytes.

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Ectopic vessel connections with the pulmonary artery lumen can form in t...
(A–C) Confocal images of pulmonary artery outflow tract explants cultured alone or adjacent to other tissues. Endothelial cells are labeled in blue (VE-cadherin+), and cardiomyocytes are labeled in red (cTnT+). Schematics summarizing experimental setup and results are shown. (A) Pulmonary artery explants retain a luminal endothelial layer that does not sprout into the vessel-free zone (dotted line). (B) Endothelial cells within lung tissue do not connect with the pulmonary artery lumen but do migrate into the myocardial (myo) region at its base (arrow), which contains cardiomyocytes. (C) When cardiomyocytes from ventricular myocardium (ven myo) are placed alongside artery explants, ventricular coronary vessels frequently form connections (arrowhead) with the pulmonary artery endothelium. (D) Percentage of explant samples that did or did not form connections with the pulmonary artery lumen when cultured beside lung or ventricular myocardium. Scale bars: 100 μm (left and center panels in A–C); 25 μm (right panels in A–C).