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SEMA3G regulates BMP9 inhibition of VEGF-mediated migration and network formation in pulmonary endothelial cells.

Published version
Peer-reviewed

Repository DOI


Type

Article

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Authors

Mirza, Sarah L 
Upton, Paul D 
Hodgson, Joshua 
Gräf, Stefan 
Morrell, Nicholas W 

Abstract

AIMS: Bone morphogenetic protein-9 (BMP9) is critical for bone morphogenetic protein receptor type-2 (BMPR2) signalling in pulmonary vascular endothelial cells. Furthermore, human genetics studies support the central role of disrupted BMPR2 mediated BMP9 signalling in vascular endothelial cells in the initiation of pulmonary arterial hypertension (PAH). In addition, loss-of-function mutations in BMP9 have been identified in PAH patients. BMP9 is considered to play an important role in vascular homeostasis and quiescence. METHODS AND RESULTS: We identified a novel BMP9 target as the class-3 semaphorin, SEMA3G. Although originally identified as playing a role in neuronal development, class-3 semaphorins may have important roles in endothelial function. Here we show that BMP9 transcriptional regulation of SEMA3G occurs via ALK1 and the canonical Smad pathway, requiring both Smad1 and Smad5. Knockdown studies demonstrated redundancy between type-2 receptors in that BMPR2 and ACTR2A were compensatory. Increased SEMA3G expression by BMP9 was found to be regulated by the transcription factor, SOX17. Moreover, we observed that SEMA3G regulates VEGF signalling by inhibiting VEGFR2 phosphorylation and that VEGF, in contrast to BMP9, negatively regulated SEMA3G transcription. Functional endothelial cell assays of VEGF-mediated migration and network formation revealed that BMP9 inhibition of VEGF was abrogated by SEMA3G knockdown. Conversely, treatment with recombinant SEMA3G partially mimicked the inhibitory action of BMP9 in these assays. CONCLUSIONS: This study provides further evidence for the anti-angiogenic role of BMP9 in microvascular endothelial cells and these functions are mediated at least in part via SOX17 and SEMA3G induction.

Description

Keywords

Angiogenesis, Endothelial cells, bone morphogenetic protein, Migration, Pulmonary arterial hypertension, Semaphorin 3 g, Vascular endothelial growth factor, Humans, Cell Movement, Semaphorins, Growth Differentiation Factor 2, Endothelial Cells, Signal Transduction, Vascular Endothelial Growth Factor A, Smad5 Protein, Activin Receptors, Type I, Bone Morphogenetic Protein Receptors, Type II, Smad1 Protein, Lung, Neovascularization, Physiologic, Cells, Cultured

Journal Title

Vascul Pharmacol

Conference Name

Journal ISSN

1537-1891
1879-3649

Volume Title

155

Publisher

Elsevier BV
Sponsorship
British Heart Foundation (RG/19/3/34265)