Venous identity requires BMP signalling through ALK3

Venous endothelial cells are molecularly and functionally distinct from their arterial counterparts. Although veins are often considered the default endothelial state, genetic manipulations can modulate both acquisition and loss of venous fate, suggesting that venous identity is the result of active...

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Published in:Nature communications Vol. 10; no. 1; pp. 453 - 18
Main Authors: Neal, Alice, Nornes, Svanhild, Payne, Sophie, Wallace, Marsha D., Fritzsche, Martin, Louphrasitthiphol, Pakavarin, Wilkinson, Robert N., Chouliaras, Kira M., Liu, Ke, Plant, Karen, Sholapurkar, Radhika, Ratnayaka, Indrika, Herzog, Wiebke, Bond, Gareth, Chico, Tim, Bou-Gharios, George, De Val, Sarah
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 28.01.2019
Nature Publishing Group
Nature Portfolio
Subjects:
13/1
13/51
38/15
38/77
45/15
631/136/16/1986
631/136/2060/16
631/337/572/2102
64/116
64/60
Animals
Animals, Genetically Modified
Binding
Bone Morphogenetic Protein Receptors, Type I - genetics
Bone Morphogenetic Protein Receptors, Type I - metabolism
Bone morphogenetic proteins
Bone Morphogenetic Proteins - genetics
Bone Morphogenetic Proteins - metabolism
Cell signaling
Coronary vessels
Embryos
Endothelial cells
Endothelial Cells - metabolism
Endothelium
Gene expression
Gene Expression Regulation, Developmental
Gene regulation
Humanities and Social Sciences
Kinases
Mice, Knockout
Mice, Transgenic
Morphology
multidisciplinary
Proteins
Receptor, EphB4 - genetics
Receptor, EphB4 - metabolism
Science
Science (multidisciplinary)
Signal Transduction - genetics
Signaling
Smad protein
Smad1 Protein - genetics
Smad1 Protein - metabolism
Smad5 protein
Smad5 Protein - genetics
Smad5 Protein - metabolism
Transcription
Transforming Growth Factor beta - genetics
Transforming Growth Factor beta - metabolism
Vascular endothelial growth factor
Veins
Veins & arteries
Veins - embryology
Veins - metabolism
Zebrafish
Zebrafish - embryology
Zebrafish - genetics
Zebrafish - metabolism
Zebrafish Proteins - genetics
Zebrafish Proteins - metabolism
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary:Venous endothelial cells are molecularly and functionally distinct from their arterial counterparts. Although veins are often considered the default endothelial state, genetic manipulations can modulate both acquisition and loss of venous fate, suggesting that venous identity is the result of active transcriptional regulation. However, little is known about this process. Here we show that BMP signalling controls venous identity via the ALK3/BMPR1A receptor and SMAD1/SMAD5. Perturbations to TGF-β and BMP signalling in mice and zebrafish result in aberrant vein formation and loss of expression of the venous-specific gene Ephb4 , with no effect on arterial identity. Analysis of a venous endothelium-specific enhancer for Ephb4 shows enriched binding of SMAD1/5 and a requirement for SMAD binding motifs. Further, our results demonstrate that BMP/SMAD-mediated Ephb4 expression requires the venous-enriched BMP type I receptor ALK3/BMPR1A. Together, our analysis demonstrates a requirement for BMP signalling in the establishment of Ephb4 expression and the venous vasculature. The establishment of functional vasculatures requires the specification of newly formed vessels into veins and arteries. Here, Neal et al. use a combination of genetic approaches in mice and zebrafish to show that BMP signalling, via ALK3 and SMAD1/5, is required for venous specification during blood vessel development.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-019-08315-w