Dissection of angiogenic signaling in zebrafish using a chemical genetic approach.
Striking homology between signaling molecules in zebrafish and humans suggests that compounds known to inhibit human kinases may enable a chemical genetic approach to dissect signaling pathways in the zebrafish embryo. We tested this hypothesis using a vascular endothelial growth factor receptor inhibitor, PTK787/ZK222584. Zebrafish embryos treated with this compound lacked all major blood vessels. Overexpression of AKT/PKB, a putative effector of vascular endothelial growth factor signaling, allowed blood vessels to form in the presence of drug. Endothelial cell apoptosis induced by the drug is prevented by increasing AKT/PKB activity, thus establishing the physiological relevance of AKT/PKB in the angiogenic process. This approach allowed us to examine the effects of blood flow and the role of endothelial signals in organogenesis.
Chan
Joanne
J
Department of Cancer Biology, Dana-Farber Cancer Institute and the Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA. jochan@mbcrr.harvard.edu
Bayliss
Peter E
PE
Wood
Jeanette M
JM
Roberts
Thomas M
TM
D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D018076:DNA, Complementary; D004625:Embryo, Nonmammalian / Q000098:blood supply*; D004730:Endothelium, Vascular / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D008969:Molecular Sequence Data; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010793:Phthalazines / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D012313:RNA / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation; D015027:Zebrafish / Q000196:embryology*
D020533:Angiogenesis Inhibitors; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D010793:Phthalazines; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D017978:Receptors, Growth Factor; C404768:vatalanib; D012313:RNA; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt