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 4

Aorta-specific cardiomyocyte development precedes CA stem formation.

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Aorta-specific cardiomyocyte development precedes CA stem formation. (A)...
(A) Confocal image of the right lateral side of an E13.5 heart showing that cardiomyocytes (red, arrowheads) develop on the aorta distal to the valves but are absent in the analogous region of the pulmonary artery. The right coronary sinus (rcs) and noncoronary sinus (ncs) regions are indicated by square and curly brackets, respectively. (B) Quantification of cardiomyocytes within the aorta and pulmonary artery. (C) Quantification of cardiomyocytes among the different regions of the aorta. (D) Right and left lateral views of the aorta showing concentration of cardiomyocytes specifically around the right and left coronary sinuses (lcs) at the maturing stem sites (arrowheads). (E) Cardiomyocytes (arrowheads) are present in the aortic wall around the right and left coronary sinuses at E11.5 before stem formation. Aortic and pulmonary valve sinuses are schematized with dotted lines. (F) Cardiomyocytes directly contact the aortic endothelium (arrowhead) where aortic sprouts (sp) form — (G) but not the pulmonary artery (arrow), which never sprouts — as quantified in H. High-magnification views of the boxed regions are shown. (I) Developing CA stems (arrowhead) are closely associated with aortic cardiomyocytes. (J) Aortic cardiomyocytes are no longer present in adult hearts. (K) Developing human CA stems (arrowheads, dotted lines) are associated with aortic cardiomyocytes. OFT, outflow tract. All data represent mean ± SD. Each dot represents a value obtained from one sample. ****P < 0.0001; ***P = 0.0001 to 0.001; **P = 0.001 to 0.01. Scale bars: 100 μm (A, D, E, left panel in F, right panel in G, J, and K); 25 μm (right panel in F and left panel in G); 50 μm (I).