title: FoxP1 stimulates angiogenesis by repressing the inhibitory guidance protein semaphorin 5B in endothelial cells.
abstract: Forkhead box (Fox) transcription factors are important regulators of cardiovascular development and several Fox-proteins have recently been shown to modulate embryonic and post-natal angiogenesis. However, the role of the FoxP subfamily, which is highly expressed in cardiovascular tissue, has not been investigated so far. Here, we show that the transcription factor FoxP1 is the highest expressed FoxP-protein in endothelial cells and that it is upregulated at the site of neovascularization during hindlimb ischemia in mice. Silencing of FoxP1 results in a strong inhibition of proliferation, tube formation and migration of cultured endothelial cells. Accordingly, knockdown of FoxP1 in zebrafish was followed by a disruption of intersomitic vascular formation. Using gene expression profiling, we show that FoxP1 induces a specific change of the endothelial transcriptome and functions as a suppressor of semaphorin 5B, which has previously been described as a neuronal inhibitory factor. Our findings now demonstrate that semaphorin 5B also acts as a FoxP1- dependent suppressor of endothelial cell proliferation, migration and sprouting, mediating the effects of FoxP1. In summary, our data indicate that the transcription factor FoxP1 is essential for the angiogenic function of endothelial cells and functions as a suppressor of the inhibitory guidance cue semaphorin 5B, suggesting an important function of FoxP1 in the regulation of neovascularization.
authors.affiliation: Department of Cardiology and Angiology I, University Heart Centre Freiburg - Bad Krozingen, Freiburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Grundmann
authors.forename: Christian
authors.initials: C
authors.lastname: Lindmayer
authors.forename: Felix P
authors.initials: FP
authors.lastname: Hans
authors.forename: Imo
authors.initials: I
authors.lastname: Hoefer
authors.forename: Thomas
authors.initials: T
authors.lastname: Helbing
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
authors.forename: Christoph
authors.initials: C
authors.lastname: Bode
authors.forename: Dominique
authors.initials: D
authors.lastname: de Kleijn
authors.forename: Martin
authors.initials: M
authors.lastname: Moser
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006614:Hindlimb / Q000378:metabolism / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007511:Ischemia / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D039961:Semaphorins / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish
chemical_list: C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; C432917:Foxp1 protein, mouse; D008562:Membrane Glycoproteins; D012097:Repressor Proteins; C409766:SEMA3B protein, human; D039961:Semaphorins
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