GATA6 promotes angiogenic function and survival in endothelial cells by suppression of autocrine transforming growth factor beta/activin receptor-like kinase 5 signaling.

2.50
Hdl Handle:
http://hdl.handle.net/10033/142831
Title:
GATA6 promotes angiogenic function and survival in endothelial cells by suppression of autocrine transforming growth factor beta/activin receptor-like kinase 5 signaling.
Authors:
Froese, Natali; Kattih, Badder; Breitbart, Astrid; Grund, Andrea; Geffers, Robert; Molkentin, Jeffery D; Kispert, Andreas; Wollert, Kai C; Drexler, Helmut; Heineke, Joerg
Abstract:
Understanding the transcriptional regulation of angiogenesis could lead to the identification of novel therapeutic targets. We showed here that the transcription factor GATA6 is expressed in different human primary endothelial cells as well as in vascular endothelial cells of mice in vivo. Activation of endothelial cells was associated with GATA6 nuclear translocation, chromatin binding, and enhanced GATA6-dependent transcriptional activation. siRNA-mediated down-regulation of GATA6 after growth factor stimulation led to a dramatically reduced capacity of macro- and microvascular endothelial cells to proliferate, migrate, or form capillary-like structures on Matrigel. Adenoviral overexpression of GATA6 in turn enhanced angiogenic function, especially in cardiac endothelial microvascular cells. Furthermore, GATA6 protected endothelial cells from undergoing apoptosis during growth factor deprivation. Mechanistically, down-regulation of GATA6 in endothelial cells led to increased expression of transforming growth factor (TGF) β1 and TGFβ2, whereas enhanced GATA6 expression, accordingly, suppressed Tgfb1 promoter activity. High TGFβ1/β2 expression in GATA6-depleted endothelial cells increased the activation of the activin receptor-like kinase 5 (ALK5) and SMAD2, and suppression of this signaling axis by TGFβ neutralizing antibody or ALK5 inhibition restored angiogenic function and survival in endothelial cells with reduced GATA6 expression. Together, these findings indicate that GATA6 plays a crucial role for endothelial cell function and survival, at least in part, by suppressing autocrine TGFβ expression and ALK5-dependent signaling.
Affiliation:
Medizinische Hochschule Hannover, Klinik für Kardiologie und Angiologie, Institut für Molekularbiologie, Rebirth-Cluster of Excellence, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
Citation:
GATA6 promotes angiogenic function and survival in endothelial cells by suppression of autocrine transforming growth factor beta/activin receptor-like kinase 5 signaling. 2011, 286 (7):5680-90 J. Biol. Chem.
Journal:
The Journal of biological chemistry
Issue Date:
18-Feb-2011
URI:
http://hdl.handle.net/10033/142831
DOI:
10.1074/jbc.M110.176925
PubMed ID:
21127043
Type:
Article
Language:
en
ISSN:
1083-351X
Appears in Collections:
publications of the TwinCore unit Infection immunology

Full metadata record

DC FieldValue Language
dc.contributor.authorFroese, Natalien
dc.contributor.authorKattih, Badderen
dc.contributor.authorBreitbart, Astriden
dc.contributor.authorGrund, Andreaen
dc.contributor.authorGeffers, Roberten
dc.contributor.authorMolkentin, Jeffery Den
dc.contributor.authorKispert, Andreasen
dc.contributor.authorWollert, Kai Cen
dc.contributor.authorDrexler, Helmuten
dc.contributor.authorHeineke, Joergen
dc.date.accessioned2011-09-21T12:50:32Z-
dc.date.available2011-09-21T12:50:32Z-
dc.date.issued2011-02-18-
dc.identifier.citationGATA6 promotes angiogenic function and survival in endothelial cells by suppression of autocrine transforming growth factor beta/activin receptor-like kinase 5 signaling. 2011, 286 (7):5680-90 J. Biol. Chem.en
dc.identifier.issn1083-351X-
dc.identifier.pmid21127043-
dc.identifier.doi10.1074/jbc.M110.176925-
dc.identifier.urihttp://hdl.handle.net/10033/142831-
dc.description.abstractUnderstanding the transcriptional regulation of angiogenesis could lead to the identification of novel therapeutic targets. We showed here that the transcription factor GATA6 is expressed in different human primary endothelial cells as well as in vascular endothelial cells of mice in vivo. Activation of endothelial cells was associated with GATA6 nuclear translocation, chromatin binding, and enhanced GATA6-dependent transcriptional activation. siRNA-mediated down-regulation of GATA6 after growth factor stimulation led to a dramatically reduced capacity of macro- and microvascular endothelial cells to proliferate, migrate, or form capillary-like structures on Matrigel. Adenoviral overexpression of GATA6 in turn enhanced angiogenic function, especially in cardiac endothelial microvascular cells. Furthermore, GATA6 protected endothelial cells from undergoing apoptosis during growth factor deprivation. Mechanistically, down-regulation of GATA6 in endothelial cells led to increased expression of transforming growth factor (TGF) β1 and TGFβ2, whereas enhanced GATA6 expression, accordingly, suppressed Tgfb1 promoter activity. High TGFβ1/β2 expression in GATA6-depleted endothelial cells increased the activation of the activin receptor-like kinase 5 (ALK5) and SMAD2, and suppression of this signaling axis by TGFβ neutralizing antibody or ALK5 inhibition restored angiogenic function and survival in endothelial cells with reduced GATA6 expression. Together, these findings indicate that GATA6 plays a crucial role for endothelial cell function and survival, at least in part, by suppressing autocrine TGFβ expression and ALK5-dependent signaling.en
dc.language.isoenen
dc.subject.meshAnimalsen
dc.subject.meshApoptosisen
dc.subject.meshAutocrine Communicationen
dc.subject.meshCells, Cultureden
dc.subject.meshEndothelial Cellsen
dc.subject.meshGATA6 Transcription Factoren
dc.subject.meshGene Expression Regulationen
dc.subject.meshHumansen
dc.subject.meshMiceen
dc.subject.meshNeovascularization, Physiologicen
dc.subject.meshProtein-Serine-Threonine Kinasesen
dc.subject.meshReceptors, Transforming Growth Factor betaen
dc.subject.meshSignal Transductionen
dc.subject.meshSmad2 Proteinen
dc.subject.meshTransforming Growth Factor beta1en
dc.subject.meshTransforming Growth Factor beta2en
dc.titleGATA6 promotes angiogenic function and survival in endothelial cells by suppression of autocrine transforming growth factor beta/activin receptor-like kinase 5 signaling.en
dc.typeArticleen
dc.contributor.departmentMedizinische Hochschule Hannover, Klinik für Kardiologie und Angiologie, Institut für Molekularbiologie, Rebirth-Cluster of Excellence, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.en
dc.identifier.journalThe Journal of biological chemistryen
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