The formation of new blood vessels is a critical part of processes as diverse as wound healing, tumor growth and embryo development. The endothelial cells lining these vessels are bound to each other through both adherens junctions and tight junctions. Within the adherens junction, the most abundant protein present is the endothelial-specific vascular endothelial cadherin. While the extracellular portion of VE-cadherin is critical for endothelial cell adhesion, its short cytoplasmic tail also provides a link to the actin cytoskeleton through associated junctional proteins such as b-catenin, plakoglobin and p120. The interaction between VE-cadherin and junctional proteins modulates endothelial cell activation and migration in response to growth factors. Exposure of cultured endothelial cells to growth factors and cytokines BIX-01294 increases tyrosine phosphorylation of VEcad, and increases endothelial permeability and migration. While much progress has occurred in elucidating the mechanisms of VE-cadherin signaling in vitro, no robust model exists to investigate these mechanisms in vivo. In mouse, VE-cad is expressed in hemangioblasts at gestational day E7.5 and soon after in all endothelial cells. Knockout of VE-cad in mice is lethal in utero at E9.25�C9.5, when the pups suffer circulatory arrest. The loss of VE-cad in these embryos does not significantly affect primary vasculogenesis, however vessel MAK683 sprouting and remodeling is severely impaired. Whether this knockout produces a cardiac-specific effect remains unclear, as defects in heart formation occur concomitant with endothelial collapse and circulatory failure. Recently, a zebrafish orthologue of VE-cadherin has been identified and its expression documented by 12 hours post fertilization. In this study, we demonstrate successful knockdown of zebrafish VE-cadherin using a translation-start site morpholino and analyze its effects on cardiovascular development, function and structure. Surprisingly, we find that while vascular development and sprouting are unaffected by VE-cadherin knockdown, cardiac looping, circulation and endocardial/myocardial adhesion are impaired.