Embryonic coronary vasculogenesis and angiogenesis are regulated by interactions between multiple FGFs and VEGF and are influenced by mesenchymal stem cells

Abstract

In embryonic hearts explanted on collagen gels, epicardial cells delaminate and form vascular tubes, thus providing a model for coronary tubulogenesis. Using this model, we show that fibroblast growth factors (FGFs) 1, 2, 4, 8, 9, and 18 contribute to tubulogenesis and that the availability of multiple FGFs provides the optimal tubulogenic response. Moreover, the FGF effects are vascular endothelial growth factor (VEGF) -dependent, while VEGF-induced tubulogenesis requires FGF signaling. The number of endothelial cells (ECs) is increased by all of the FGFs, while EC migration is significantly enhanced only by FGF-2 and FGF-18. Finally, addition of embryonic mesenchymal stem cells (EMSC) to the explants markedly enhances EC numbers and a 23-fold increase in stromal derived factor-1α (SDF-1α), which is FGF dependent. Both explants and EMSCs produce SDF-1α. In conclusion, coronary tubulogenesis of embryonic epicardium: (1) is responsive to many FGF family members, (2) requires both FGF and VEGFA signaling, and (3) is responsive to EMSCs.