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PMID:18579532

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Citation

Hayashi, H, Sano, H, Seo, S and Kume, T (2008) The Foxc2 transcription factor regulates angiogenesis via induction of integrin beta3 expression. J. Biol. Chem. 283:23791-800

Abstract

Forkhead transcription factor Foxc2 is an essential regulator of the cardiovascular system in development and disease. However, the cellular and molecular functions of Foxc2 in vascular endothelial cells are still not fully understood. Here, through gene expression profiling in endothelial cells, we identified molecules associated with cell-extracellular matrix interactions, integrin beta3 (Itgb3), integrin beta5 (Itgb5), and fibronectin, as downstream targets of Foxc2. We found that Itgb3 expression is directly regulated by Foxc2 through multiple Forkhead-binding elements within two high homology regions in the Itgb3 promoter. Because Itgb3 is known to regulate angiogenesis, we further tested whether Foxc2 is directly involved in angiogenesis by regulating Itgb3 expression by in vitro experiments. Overexpression of Foxc2 significantly enhanced endothelial cell migration and adhesion, whereas this effect was strongly inhibited by Itgb3 neutralization antibody. In accordance with these results, pulmonary microvascular endothelial cells isolated from Foxc2 heterozygous mutant mice showed a marked reduction in Itgb3 expression and cell migration. Finally, ex vivo aortic ring assay to test the sprouting and microvessel formation revealed enhanced microvessel outgrowth by Foxc2 overexpression. Conversely, microvessel outgrowth from aortas of Foxc2 heterozygous mutant mice was reduced. Taken together, these results suggest that Foxc2 directly induces Itgb3 expression and regulates angiogenesis by Itgb3-mediated endothelial cell adhesion and migration.

Links

PubMed PMC2527100 Online version:10.1074/jbc.M800190200

Keywords

Animals; Cell Adhesion/physiology; Cell Line; Cell Movement/physiology; Endothelial Cells/cytology; Endothelial Cells/metabolism; Forkhead Transcription Factors/genetics; Forkhead Transcription Factors/metabolism; Gene Expression Regulation/physiology; Integrin beta Chains/biosynthesis; Integrin beta Chains/genetics; Integrin beta3/biosynthesis; Integrin beta3/genetics; Lung/blood supply; Lung/metabolism; Mice; Mice, Mutant Strains; Neovascularization, Physiologic/physiology; Response Elements/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:FOXC1

enables

GO:0000976: transcription cis-regulatory region binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:FOXC1

enables

GO:0003700: DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:FOXC1

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FOXC2

enables

GO:0000976: transcription cis-regulatory region binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:FOXC2

GO:0033625: positive regulation of integrin activation

ECO:0000314:

P

Figure 1A: Foxc2 induces the expression of Itgb3 and Itgb5, (components of avβ3 and �αvβ5 integrin heterodimers respectively) and fibronectin (FN) a ligand for integrin avβ3.

complete

MOUSE:FOXC2

GO:0010843: promoter binding

ECO:0000314:

F

Figure 3C: Foxc2 activates the proximal Itgb3 promoter in a dose-dependent manner.

complete

MOUSE:FOXC2

GO:0001937: negative regulation of endothelial cell proliferation

ECO:0000314:

P

Figure 4: Although VEGF augmented cell division Foxc2 overexpression along with VEGF did not show further increase in proliferation compared with the control VEGF cells. This indicates that Foxc2 does not stimulate the proliferation of endothelial cells

complete

MOUSE:FOXC2

GO:0033627: cell adhesion mediated by integrin

ECO:0000314:

P

Figure 5A: Adhesion assays showed that Foxc2 significantly increased adhesiveness compared with the control cells.

complete

MOUSE:FOXC2

GO:0010595: positive regulation of endothelial cell migration

ECO:0000314:

P

Figure 5C: Wound close assay showed that Foxc2 enhanced endothelial cell migration

complete

MOUSE:FOXC2

GO:0045941: positive regulation of transcription

ECO:0000314:

P

Figure 3E: Foxc2 directly induces Itgb3 expression through Itgb3 distal and proximal HHRs in endothelial cells

complete

MOUSE:FOXC2

GO:0090050 : positive regulation of cell migration involved in sprouting angiogenesis

ECO:0000314:

P

Figure 7A: The aortic ring assay showed abundant formation of vascular sprouts from aortic rings infected with Ad-Foxc2 compared with the control

complete

MOUSE:FOXC2

GO:0035470:

ECO:0000314:

Figure 5B-C: Wound closure assays showed that Foxc2 dramatically enhanced endothelial cell migration

complete

MOUSE:FOXC2

involved_in

GO:0010595: positive regulation of endothelial cell migration

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FOXC2

involved_in

GO:0033625: positive regulation of integrin activation

ECO:0000305: curator inference used in manual assertion

GO:0045944

P

Seeded From UniProt

complete

MOUSE:FOXC2

involved_in

GO:0033630: positive regulation of cell adhesion mediated by integrin

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FOXC2

involved_in

GO:0035470: positive regulation of vascular wound healing

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FOXC2

enables

GO:0044212: transcription regulatory region DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:FOXC2

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FOXC2

involved_in

GO:0090050: positive regulation of cell migration involved in sprouting angiogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FOXC2

enables

GO:0003700: DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:FOXC2

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:FOXF1

GO:0010843: promoter binding

ECO:0000314:

F

Supplamentary Figure 3: Foxf1 activates the Itbg3 promoter and regulates its expression.

complete

MOUSE:LAMP2

acts_upstream_of_or_within

GO:0061684: chaperone-mediated autophagy

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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