The sinus venosus contributes to coronary vasculature through VEGFC-stimulated angiogenesis

Abstract

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 lineagetracing 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 (endocardialderived) 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.

VEGF-C and aortic cardiomyocytes guide coronary artery stem development

“…Myocardial thickness and valve structure are not perturbed in knockout hearts, which is consistent with the more restricted expression pattern of VEGF-C in the outflow tract vessels and epicardium (26). In another study, we showed that VEGF-C deletion specifically affects sinus venosus-derived coronary development but not coronary vascularization from other sources on the ventral side of the heart and septum (likely from the endocardium, refs.…”

“…Depletion of VEGF-C had a dramatic effect. Although heart morphogenesis was grossly normal and other vessel beds were not affected (26), ASVs were completely missing and peritruncal coronary vessels were severely reduced in VEGF-C knockout animals ( Figure 3E). Heterozygous animals exhibited an intermediate phenotype (Figure 3F).…”

“…Coronary vessels originate from at least 3 progenitor populations, the sinus venosus (25,26), endocardium (25,27), and proepicardium (28), the latter of which may first transition through the former cell types (28). We next performed Cre recombinase-based lineage tracing with Cre lines expressed in the sinus venosus and endocardium to assess their contribution to CA stems.…”

Developmental origin and lineage plasticity of endogenous cardiac stem cells

“…Although the perivascular compartment of coronary vessels appears to derive from the epicardium (including resident CD45 + cells), recent lineage-tracing studies show that coronary endothelial cells have heterogeneous origins. The details are still being debated, but it is clear that distinct populations of endothelial cells arise from the sinus venosus and the endocardium, with a minor population deriving directly from the epicardium (Chen et al, 2014;Del Monte and Harvey, 2012;Katz et al, 2012;Tian et al, 2014;Wu et al, 2012). These populations deploy angioblasts with distinct kinetics and spatial signatures (Chen et al, 2014), with the endocardium also contributing to the coronary vascular tree postnatally during a process called trabecular compaction (Tian et al, 2014).…”

“…The details are still being debated, but it is clear that distinct populations of endothelial cells arise from the sinus venosus and the endocardium, with a minor population deriving directly from the epicardium (Chen et al, 2014;Del Monte and Harvey, 2012;Katz et al, 2012;Tian et al, 2014;Wu et al, 2012). These populations deploy angioblasts with distinct kinetics and spatial signatures (Chen et al, 2014), with the endocardium also contributing to the coronary vascular tree postnatally during a process called trabecular compaction (Tian et al, 2014). Cardiac lymphatics also have a dual origin from the endothelial cells of the cardinal veins, as well as yolk sac endothelial or hemogenic cells (Klotz et al, 2015).…”