Relationship between vascular development and vascular differentiation during liver organogenesis in humans

Backgrounds/Aims: The complex vascular architecture characteristic of the normal adult liver is progressively acquired during the fetal life. In this study, we aimed to evaluate the relationship between angiogenesis and vascular differentiation during liver organogenesis. Methods: We studied, in 51 fetuses of different gestational ages, the expression of markers of endothelial cell differentiation, integrins, pro- and anti-angiogenic extracellular matrix components, vascular endothelial growth factor (VEGF) and its receptors. Results: Three main stages in the development of the vascular architecture of the liver were identified: (a) from 5 to 10 gestation weeks (GW), no evidence of de novo angiogenesis was detected; the vessels present in the liver primordium were the precursors of portal veins and sinusoids, deriving from preexisting vessels; (b) from 10 to 25 GW, angiogenesis and vasculogenesis resulted in the development of, respectively, arteries and intra-portal capillaries, while portal veins and hepatic sinusoids followed a differentiation process; (c) after 25 GW, little changes were detected in the various vascular compartments. The maximal expression of VEGF and its receptors was from 5 to 25 GW. Conclusions: The development of the hepatic vascular architecture is a multistep process combining angiogenesis, vasculogenesis and vascular differentiation, regulated by specific growth and differentiation factors including VEGF.