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PMID:17992660

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Citation

Southwood, M, Jeffery, TK, Yang, X, Upton, PD, Hall, SM, Atkinson, C, Haworth, SG, Stewart, S, Reynolds, PN, Long, L, Trembath, RC and Morrell, NW (2008) Regulation of bone morphogenetic protein signalling in human pulmonary vascular development. J. Pathol. 214:85-95

Abstract

The bone morphogenetic protein (BMP) type II receptor (BMPR-II) is predominantly expressed on the vascular endothelium in the adult lung. Although mutations in BMPR-II are known to underlie many cases of familial pulmonary arterial hypertension (FPAH), little is known regarding the expression of BMPs and their signalling pathways during normal lung development or the impact of BMPR-II mutations on endothelial cell function. We determined the cellular localization and expression levels of BMP4, BMP receptors, and activation of downstream signalling via phospho-Smad1 in a developmental series of human embryonic and fetal lungs by immunohistochemistry. The expression of BMP4 and BMP receptors was temporally and spatially regulated during lung development. BMPR-II expression correlated with phosphorylation of tissue Smad1 and was highest during the late pseudoglandular and early canalicular stage of lung development, when vasculogenesis is intense. Phospho-Smad1 expression was associated with markers of proliferation in endothelial cells. In vitro studies confirmed that BMPs 2 and 4 induced phosphorylation of Smad1/5 and pulmonary artery endothelial cell (PAEC) migration and proliferation. Adenoviral transfection of PAECs with mutant kinase-deficient BMPR-II, or siRNA knockdown of BMPR-II, inhibited Smad signalling and the proliferative response to BMP4. Our findings support a critical role for BMPs in lung vasculogenesis. Dysfunctional BMP signalling in PAECs during development may lead to abnormal pulmonary vascular development and contribute to the pathogenesis of FPAH.

Links

PubMed Online version:10.1002/path.2261

Keywords

Bone Morphogenetic Protein 4; Bone Morphogenetic Protein Receptors, Type II/genetics; Bone Morphogenetic Protein Receptors, Type II/metabolism; Bone Morphogenetic Proteins/genetics; Bone Morphogenetic Proteins/metabolism; Bone Morphogenetic Proteins/physiology; Cell Movement/physiology; Cell Proliferation; Cell Survival/physiology; Cells, Cultured; Endothelium, Vascular/metabolism; Fetal Development/physiology; Gene Expression Regulation, Developmental/physiology; Gene Silencing; Humans; Immunoenzyme Techniques; Lung/embryology; Pulmonary Alveoli/embryology; Pulmonary Artery/metabolism; Pulmonary Circulation/physiology; Reverse Transcriptase Polymerase Chain Reaction/methods; Signal Transduction

Significance

Annotations

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

HUMAN:BMP2

involved_in

GO:0001938: positive regulation of endothelial cell proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP2

involved_in

GO:0010862: positive regulation of pathway-restricted SMAD protein phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0043410: positive regulation of MAPK cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMPR2

involved_in

GO:0030513: positive regulation of BMP signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMPR2

involved_in

GO:0010862: positive regulation of pathway-restricted SMAD protein phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMPR2

involved_in

GO:0010595: positive regulation of endothelial cell migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMPR2

involved_in

GO:0001938: positive regulation of endothelial cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0000186: activation of MAPKK activity

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0010862: positive regulation of pathway-restricted SMAD protein phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0001938: positive regulation of endothelial cell proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0010595: positive regulation of endothelial cell migration

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0043066: negative regulation of apoptotic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0061155: pulmonary artery endothelial tube morphogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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