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PMID:18787191

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Citation

Heinke, J, Wehofsits, L, Zhou, Q, Zoeller, C, Baar, KM, Helbing, T, Laib, A, Augustin, H, Bode, C, Patterson, C and Moser, M (2008) BMPER is an endothelial cell regulator and controls bone morphogenetic protein-4-dependent angiogenesis. Circ. Res. 103:804-12

Abstract

Bone morphogenetic proteins (BMPs) are involved in embryonic and adult blood vessel formation in health and disease. BMPER (BMP endothelial cell precursor-derived regulator) is a differentially expressed protein in embryonic endothelial precursor cells. In earlier work, we found that BMPER interacts with BMPs and when overexpressed antagonizes their function in embryonic axis formation. In contrast, in a BMPER-deficient zebrafish model, BMPER behaves as a BMP agonist. Furthermore, lack of BMPER induces a vascular phenotype in zebrafish that is driven by disarray of the intersomitic vasculature. Here, we investigate the impact of BMPER on endothelial cell function and signaling and elucidate its role in BMP-4 function in gain- and loss-of-function models. As shown by Western blotting and immunocytochemistry, BMPER is an extracellular matrix protein expressed by endothelial cells in skin, heart, and lung. We show that BMPER is a downstream target of FoxO3a and consistently exerts activating effects on endothelial cell sprouting and migration in vitro and in vivo. Accordingly, when BMPER is depleted from endothelial cells, sprouting is impaired. In terms of BMPER related intracellular signaling, we show that BMPER is permissive and necessary for Smad 1/5 phosphorylation and induces Erk1/2 activation. Most interestingly, BMPER is necessary for BMP-4 to exert its activating role in endothelial function and to induce Smad 1/5 activation. Vice versa, BMP-4 is necessary for BMPER activity. Taken together, BMPER is a dose-dependent endothelial cell activator that plays a unique and pivotal role in fine-tuning BMP activity in angiogenesis.

Links

PubMed Online version:10.1161/CIRCRESAHA.108.178434

Keywords

Animals; Apoptosis; Bone Morphogenetic Protein 4; Bone Morphogenetic Proteins/genetics; Bone Morphogenetic Proteins/metabolism; Capillaries/metabolism; Carrier Proteins/genetics; Carrier Proteins/metabolism; Cell Adhesion; Cell Movement; Cells, Cultured; Chick Embryo; Chorioallantoic Membrane/blood supply; Collagen; Drug Combinations; Endothelial Cells/metabolism; Forkhead Transcription Factors/metabolism; Humans; Laminin; Mitogen-Activated Protein Kinase 1/metabolism; Mitogen-Activated Protein Kinase 3/metabolism; Neovascularization, Physiologic; Phosphorylation; Proteoglycans; RNA Interference; RNA, Small Interfering/metabolism; Signal Transduction; Smad1 Protein/metabolism; Smad5 Protein/metabolism; Time Factors; Transfection; Zebrafish Proteins

Significance

Annotations

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

HUMAN:BMPER

involved_in

GO:0030514: negative regulation of BMP signaling pathway

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMPER

involved_in

GO:0002043: blood vessel endothelial cell proliferation involved in sprouting angiogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMPER

located_in

GO:0005615: extracellular space

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:BMPER

involved_in

GO:0010594: regulation of endothelial cell migration

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMPER

involved_in

GO:0060393: regulation of pathway-restricted SMAD protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMPER

involved_in

GO:0070374: positive regulation of ERK1 and ERK2 cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMPER

involved_in

GO:0042118: endothelial cell activation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FOXO3

involved_in

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

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0060393: regulation of pathway-restricted SMAD protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0002043: blood vessel endothelial cell proliferation involved in sprouting angiogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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