The sinus venosus contributes to coronary vasculature through VEGFC-stimulated angiogenesis.
Identifying coronary artery progenitors and their developmental pathways could inspire novel regenerative treatments for heart disease. Multiple sources of coronary vessels have been proposed, including the sinus venosus (SV), endocardium and proepicardium, but their relative contributions to the coronary circulation and the molecular mechanisms regulating their development are poorly understood. We created an ApjCreER mouse line as a lineage-tracing tool to map SV-derived vessels onto the heart and compared the resulting lineage pattern with endocardial and proepicardial contributions to the coronary circulation. The data showed a striking compartmentalization to coronary development. ApjCreER-traced vessels contributed to a large number of arteries, capillaries and veins on the dorsal and lateral sides of the heart. By contrast, untraced vessels predominated in the midline of the ventral aspect and ventricular septum, which are vessel populations primarily derived from the endocardium. The proepicardium gave rise to a smaller fraction of vessels spaced relatively uniformly throughout the ventricular walls. Dorsal (SV-derived) and ventral (endocardial-derived) coronary vessels developed in response to different growth signals. The absence of VEGFC, which is expressed in the epicardium, dramatically inhibited dorsal and lateral coronary growth but left vessels on the ventral side unaffected. We propose that complementary SV-derived and endocardial-derived migratory routes unite to form the coronary vasculature and that the former requires VEGFC, revealing its role as a tissue-specific mediator of blood endothelial development.
Department of Biological Sciences, Stanford University, Stanford, CA 94305, USA.
Heidi I
HI
Chen
Department of Biological Sciences, Stanford University, Stanford, CA 94305, USA.
Bikram
B
Sharma
Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA.
Brynn N
BN
Akerberg
Wihuri Research Institute and Translational Cancer Biology Program, University of Helsinki, Biomedicum Helsinki, 00290 Helsinki, Finland.
Harri J
HJ
Numi
Wihuri Research Institute and Translational Cancer Biology Program, University of Helsinki, Biomedicum Helsinki, 00290 Helsinki, Finland.
Riikka
R
Kivelä
Wihuri Research Institute and Translational Cancer Biology Program, University of Helsinki, Biomedicum Helsinki, 00290 Helsinki, Finland.
Pipsa
P
Saharinen
Department of Cell and Developmental Biology, The Cardiovascular Institute and Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Haig
H
Aghajanian
Department of Biological Sciences, Stanford University, Stanford, CA 94305, USA.
Andrew S
AS
McKay
Ariosa Diagnostics, Inc., San Jose, CA 95138, USA.
Patrick E
PE
Bogard
Department of Biological Sciences, Stanford University, Stanford, CA 94305, USA Department of Developmental Biology, School of Medicine, Stanford University, Stanford, CA 94305, USA.
Andrew H
AH
Chang
Department of Biological Sciences, Stanford University, Stanford, CA 94305, USA.
Andrew H
AH
Jacobs
Department of Cell and Developmental Biology, The Cardiovascular Institute and Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Jonathan A
JA
Epstein
Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA.
Kryn
K
Stankunas
Wihuri Research Institute and Translational Cancer Biology Program, University of Helsinki, Biomedicum Helsinki, 00290 Helsinki, Finland.
Kari
K
Alitalo
Department of Biological Sciences, Stanford University, Stanford, CA 94305, USA kredhors@stanford.edu.
Kristy
K
Red-Horse
D000818:Animals; D019070:Cell Lineage / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D003331:Coronary Vessels / Q000166:cytology / Q000196:embryology*; D006325:Heart Atria / Q000166:cytology / Q000196:embryology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008817:Mice, Mutant Strains; D008856:Microscopy, Fluorescence; D018919:Neovascularization, Physiologic / Q000502:physiology*; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*
D042582:Vascular Endothelial Growth Factor C; C467483:vascular endothelial growth factor C, mouse
APLNR); Angiogenesis; Apelin receptor (APJ; Coronary vessel development; Endothelium; Sinus venosus; VEGF-C