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 1

CA stem development in mice.

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CA stem development in mice. (A) Schematics showing top and right latera...
(A) Schematics showing top and right lateral views of the heart, including CA stem locations (black arrows). (B) Confocal images of the right lateral side of hearts from the indicated embryonic days labeled for VE-cadherin. Coronary vessels (cv) and ASVs (arrowheads) grow toward the future right CA stem site (red asterisk) on the aorta (ao, dotted lines). (C) Tissue section through the aorta showing the presence of ASVs (red, arrowheads) directly beneath the epicardium (WT1+, green) and a vessel-free region around the aorta. The right panel is a high-magnification view of the boxed region. (D) Luminal endothelial cells lining the aorta, but not the pulmonary artery (pa), form sprouts (arrow). Inset is a high-magnification view of the boxed region. (E) Apelin-nlacZ expression (green, arrows) in VE-cadherin+ (red) aortic endothelium and adjacent sprouts. (F–I) Image projections of the CA stem site. (F) Small endothelial extensions from the aorta (arrow). (G) Initial interactions between coronary vessels and the aorta consist of thin, single-celled connections (arrowhead). (H) Multiple, lumenized connections that receive blood flow (arrowheads) develop at the future stem site and begin to acquire smooth muscle cell (SMC) coverage. (I) The mature pattern is a single, larger bore vessel stemming from the right coronary sinus (arrowheads) directly distal to the valves. (J) CA stem development. epi, epicardium; EC, endothelial cell; L atrium, left atrium; lca, left CA; ot, outflow tract; ra, right atrium; R atrium, right atrium; r ven, right ventricle; RCA, right CA. Scale bars: 100 μm (B–D); 50 μm (F–I); 25 μm (E, right panel in C, and inset in D).