title: 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.forename: Heidi I
authors.initials: HI
authors.lastname: Chen
authors.forename: Aruna
authors.initials: A
authors.lastname: Poduri
authors.forename: Harri
authors.initials: H
authors.lastname: Numi
authors.forename: Riikka
authors.initials: R
authors.lastname: Kivela
authors.forename: Pipsa
authors.initials: P
authors.lastname: Saharinen
authors.forename: Andrew S
authors.initials: AS
authors.lastname: McKay
authors.forename: Brian
authors.initials: B
authors.lastname: Raftrey
authors.forename: Jared
authors.initials: J
authors.lastname: Churko
authors.forename: Xueying
authors.initials: X
authors.lastname: Tian
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Wu
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Kristy
authors.initials: K
authors.lastname: Red-Horse
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology*; D019521:Body Patterning; D002454:Cell Differentiation; D002465:Cell Movement; D003331:Coronary Vessels / Q000166:cytology / Q000196:embryology*; D005260:Female; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000502:physiology*; D018919:Neovascularization, Physiologic; D011651:Pulmonary Artery / Q000502:physiology; D046509:Tissue Culture Techniques; D042582:Vascular Endothelial Growth Factor C / Q000502:physiology*
chemical_list: D042582:Vascular Endothelial Growth Factor C; C467483:vascular endothelial growth factor C, mouse