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.
Lee
You Mie
YM
Vascular Biology Program, Department of Surgery, Children's Hospital, Boston, Massachusetts 02115, USA.
Cope
John J
JJ
Ackermann
Gabriele E
GE
Goishi
Katsutoshi
K
Armstrong
Ehrin J
EJ
Paw
Barry H
BH
Bischoff
Joyce
J
D000818:Animals; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006351:Heart Valves / Q000002:abnormalities / Q000187:drug effects / Q000196:embryology* / Q000502:physiology; D006801:Humans; D050778:NFATC Transcription Factors / Q000378:metabolism; D010793:Phthalazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051881:Receptor, Notch1 / Q000096:biosynthesis / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015027:Zebrafish / Q000196:embryology* / Q000502:physiology; D029961:Zebrafish Proteins
C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D050778:NFATC Transcription Factors; D010793:Phthalazines; D011725:Pyridines; D051881:Receptor, Notch1; D029961:Zebrafish Proteins; C525813:bmp4 protein, zebrafish; C404768:vatalanib; D040262:Receptors, Vascular Endothelial Growth Factor