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 7

Misplaced CA stems are correlated with aortic cardiomyocytes in hearts from Pax3-null embryos.

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Misplaced CA stems are correlated with aortic cardiomyocytes in hearts f...
(A and B) The side-by-side positioning of the aorta and pulmonary artery in hearts from (B) Pax3-null embryos compared with (A) wild-type embryos. Blue lines indicate the locations of CA stems. (C–H) Confocal images of hearts immunofluorescently labeled for VE-cadherin (endothelium) and cTnT (cardiomyocytes). CA stems (arrowheads) associate with aortic cardiomyocytes (brackets) in wild-type and in Pax3 knockouts. CA stems are outlined in solid lines in D–F. Outflow tracts are outlined with dotted lines in C–F. Images in G and H are maximum projections of optical sections through the aortic lumen captured from the right lateral side of the heart. Scale bars: 100 μm.