VEGFS, FGFS, and PDGF Coordinate Embryonic Coronary Vascularization

Abstract

The formation of the coronary vasculature during embryonic and fetal life requires many signaling events that involve transcription factors, growth factors, and other molecules. Vascular precursor cells migrate to the heart from the proepicardium, and then differentiate and assemble to form the coronary vasculature. Several growth factors are required for coronary vasculogenesis, angiogenesis, and arteriogenesis, as documented in this chapter, based on both in vitro and in vivo studies in quail, rat, and mouse. Our data reveal that formation of the initial vascular, endothelial-lined channels is regulated by multiple VEGFs (especially VEGF-B), multiple FGFs, and angiopoietins. TGF-β inhibits at least two splice variants of VEGF, thus its expression attenuates endothelial cell proliferation during arteriogenesis. Our findings also document: (1) VEGF-B and VEGFR-1 as the key players in the formation of coronary ostia and stems, and (2) FGF-2 and PDGF as important regulators of coronary arterial formation. These conclusions are based on experiments in which these growth factors were inhibited by injecting neutralizing antibodies into the vitelline vein of quail embryos. Finally, we tested the hypothesis that embryonic mesenchymal stem cells (EMSCs) facilitate coronary tubulogenesis by adding these cells to mouse embryonic heart explants. These experiments revealed an increased tubulogenesis associated with a 22-fold enhancement of stromal-derived factor-1 (SDF-1), most of which was a product of the EMSCs. In conclusion, prenatal coronary vessel development requires temporally and spatially coordinated signaling processes, multiple growth factors, and the influence of progenitor cells.