See related article, pages 1057–1064 The formation of the cardiovascular system starts in the mouse embryo at approximately embryonic day (E)7.0 to E7.5. The first blood vessels in the extraembryonic membranes, the major intraembryonic vessels, and the heart form by vasculogenesis, the in situ differentiation of mesodermal cells that give rise to “blood-islands.” The latter are composed of hemangioblasts, the common precursors of endothelial and blood cells. Hemangioblasts situated in the lumen of the blood islands will further differentiate into hematocytoblasts, the precursors of all 3 lineages of blood cells. In contrast, hemangioblasts lining the walls of the blood islands will give rise to angioblasts that form endothelial cells.1 Migrating angioblasts from the proximal lateral mesoderm assemble symmetrically at the lateral sides of the embryo to establish 2 preendocardial tubes. They fuse to give rise to the primordial heart.2 While vasculogenesis is still proceeding, the uniform blood islands begin to remodel to a network of large and small vessels by the process of angiogenesis, preferentially intussusceptive microvascular growth.3,4 Gene expression and targeting studies have identified vascular endothelial growth factor and its 2 receptors, KDR/flk-1 and flt-1, as critical for the formation and early remodeling of the blood islands. Vascular endothelial growth factor is produced by endodermal and mesodermal cells at the onset of hemangioblast formation, whereas its receptors are expressed in the future endothelial cells lining the blood islands.5 Flk-1−/− embryos lack blood islands throughout the embryo and yolk sac.6 In flt-1−/− embryos, blood islands do not properly remodel but form large blood channels.7 Inactivation of a single vascular endothelial growth factor allele caused multiple embryonic malformations including the heart, rudimentary dorsal aortae, and a reduced number of blood cells.8,9 All deletions were lethal between days E8.5 and E11 to …