title: Combination of reverse and chemical genetic screens reveals angiogenesis inhibitors and targets.
abstract: We combined reverse and chemical genetics to identify targets and compounds modulating blood vessel development. Through transcript profiling in mice, we identified 150 potentially druggable microvessel-enriched gene products. Orthologs of 50 of these were knocked down in a reverse genetic screen in zebrafish, demonstrating that 16 were necessary for developmental angiogenesis. In parallel, 1280 pharmacologically active compounds were screened in a human cell-based assay, identifying 28 compounds selectively inhibiting endothelial sprouting. Several links were revealed between the results of the reverse and chemical genetic screens, including the serine/threonine (S/T) phosphatases ppp1ca, ppp1cc, and ppp4c and an inhibitor of this gene family; Endothall. Our results suggest that the combination of reverse and chemical genetic screens, in vertebrates, is an efficient strategy for the identification of drug targets and compounds that modulate complex biological systems, such as angiogenesis.
authors.affiliation: AngioGenetics Sweden AB, Scheeles väg 2, SE 171 77 Stockholm, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Kalén
authors.forename: Elisabet
authors.initials: E
authors.lastname: Wallgard
authors.forename: Noomi
authors.initials: N
authors.lastname: Asker
authors.forename: Aidas
authors.initials: A
authors.lastname: Nasevicius
authors.forename: Elisabet
authors.initials: E
authors.lastname: Athley
authors.forename: Erik
authors.initials: E
authors.lastname: Billgren
authors.forename: Jon D
authors.initials: JD
authors.lastname: Larson
authors.forename: Shannon A
authors.initials: SA
authors.lastname: Wadman
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Norseng
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Clark
authors.forename: Liqun
authors.initials: L
authors.lastname: He
authors.forename: Linda
authors.initials: L
authors.lastname: Karlsson-Lindahl
authors.forename: Ann-Katrin
authors.initials: AK
authors.lastname: Häger
authors.forename: Holger
authors.initials: H
authors.lastname: Weber
authors.forename: Hellmut
authors.initials: H
authors.lastname: Augustin
authors.forename: Tore
authors.initials: T
authors.lastname: Samuelsson
authors.forename: Chelsy K
authors.initials: CK
authors.lastname: Kemmet
authors.forename: Carly M
authors.initials: CM
authors.lastname: Utesch
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Essner
authors.forename: Perry B
authors.initials: PB
authors.lastname: Hackett
authors.forename: Mats
authors.initials: M
authors.lastname: Hellström
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003998:Dicarboxylic Acids / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000166:cytology; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D020533:Angiogenesis Inhibitors; D003998:Dicarboxylic Acids; C100030:endothall; D010749:Phosphoprotein Phosphatases