Vascular endothelial growth factor receptor signaling is required for cardiac valve formation in zebrafish

Vascular endothelial growth factor‐receptors (VEGF‐Rs) are pivotal regulators of vascular development, but a specific role for these receptors in the formation of heart valves has not been identified. We took advantage of small molecule inhibitors of VEGF‐R signaling and showed that blocking VEGF‐R signaling with receptor selective tyrosine kinase inhibitors, PTK 787 and AAC 787, from 17–21 hr post‐fertilization (hpf) in zebrafish embryos resulted in a functional and structural defect in cardiac valve development. Regurgitation of blood between the two chambers of the heart, as well as a loss of cell‐restricted expression of the valve differentiation markers notch 1b and bone morphogenetic protein‐4 (bmp‐4), was readily apparent in treated embryos. In addition, microangiography revealed a loss of a definitive atrioventricular constriction in treated embryos. Taken together, these data demonstrate a novel function for VEGF‐Rs in the endocardial endothelium of the developing cardiac valve. Developmental Dynamics 235:29–37, 2006. © 2005 Wiley‐Liss, Inc.