Vascular development is a multistep process that initially involves vasculogenesis, the process of de novo formation of the primitive vasculature from mesodermal precursors, and angiogenesis, that involves sprouting and remodeling of the primitive vasculature.1 This is followed by vascular fate specification steps that define formation of arterial, venous, and lymphatic vasculatures.2 This complex series of steps is regulated by several growth factors and their receptors. Among them are vascular endothelial growth factors (VEGFs), angiopoietins, and Notch receptors and their ligands, Dll4 and jagged-1. Any abnormalities in this sequence of events lead to either an outright failure of vascular development or formation of abnormally patterned vasculature. The later includes arterio-venous malformations, cranial cerebral malformations, and aneurysms among others.3 Article, see p 709 Among the numerous growth factors that are involved in these phenomena, VEGF-A plays a particularly critical role and is involved both in formation of the initial primitive vascular plexus and in subsequent sprouting, remodeling, and fate specification steps.4 VEGF-A signaling input is tightly controlled so much that deletion of even a single Vegfa allele results in embryonic lethality.5,6 VEGF-A signals via its 2 tyrosine kinase receptors (VEGFRs), Flt1 (VEGFR1) and Flk1 (VEGFR2), as well as a nonreceptor tyrosine kinase neuropilin-1 (Nrp1). Deletion of VEGFR2 is embryonically lethal because of almost complete failure of vasculogenesis,7 whereas endothelial deletion of Nrp1 leads to multiple vascular abnormalities at a later stage of development.8 VEGFR1 in this context is seen mainly as a negative regulator of VEGF-A signaling. Its knockout leads to embryonic lethality because of excessive vasculogenesis and angiogenesis.9 Given the critical role that VEGF-A plays in vascular development and the tight control of its effective concentration range, much effort has been expanded to understand the mechanisms that regulate its expression. Several …