An important function of the vascular system is nutrient delivery. In adult animals, this is mediated through a close contact of the mesoderm-derived vasculature with the endoderm-derived enterocytes and hepatocytes. During embryonic development, the yolk sac (YS) endoderm has been suggested to play a similar role. Physiological and molecular nature of the contact between the YS endoderm and the vasculature is not well-understood. To understand roles of the YS endoderm in early development, we used the avian model and carried out a gene expression profiling analysis of isolated area vasculosa YS endoderm tissues from embryonic day 2–4 chick embryos, covering the first 48 hr of postcirculation development. Genes involved in lipid metabolism are highly enriched, indicating an active modification of lipid components during their transfer from the yolk to the circulatory system. We also uncovered genes encoding major serum proteins and key regulators of vascular integrity. In particular, PTGDS, an enzyme controlling the last step of prostaglandin D2 production, shows high expression in the YS endoderm. Experimental introduction of prostaglandin D2 into embryonic circulation led to intraembryonic vessel rupture. These data suggest that the YS endoderm is the major, if not exclusive, source of lipid and protein constituents of the early embryonic serum and plays an important role in the regulation of vascular integrity in developing embryo. Developmental Dynamics 240:2002–2010, 2011. © 2011 Wiley-Liss, Inc.