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Dev Biol. 2018 Oct 15;442(2):199-209. doi: 10.1016/j.ydbio.2018.07.027. Epub 2018 Aug 9.

Developmental SMAD6 loss leads to blood vessel hemorrhage and disrupted endothelial cell junctions.

Author information

1
Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
2
StrideBio, Inc., Durham, NC 27701, USA.
3
Dept. of Medicine, Duke University, Durham, NC 27710, USA.
4
Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; McAllister Heart Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: bautch@med.unc.edu.

Abstract

The BMP pathway regulates developmental processes including angiogenesis, yet its signaling outputs are complex and context-dependent. Recently, we showed that SMAD6, an intracellular BMP inhibitor expressed in endothelial cells, decreases vessel sprouting and branching both in vitro and in zebrafish. Genetic deletion of SMAD6 in mice results in poorly characterized cardiovascular defects and lethality. Here, we analyzed the effects of SMAD6 loss on vascular function during murine development. SMAD6 was expressed in a subset of blood vessels throughout development, primarily in arteries, while expression outside of the vasculature was largely confined to developing cardiac valves with no obvious embryonic phenotype. Mice deficient in SMAD6 died during late gestation and early stages of postnatal development, and this lethality was associated with vessel hemorrhage. Mice that survived past birth had increased branching and sprouting of developing postnatal retinal vessels and disorganized tight and adherens junctions. In vitro, knockdown of SMAD6 led to abnormal endothelial cell adherens junctions and increased VE-cadherin endocytosis, indicative of activated endothelium. Thus, SMAD6 is essential for proper blood vessel function during murine development, where it appears to stabilize endothelial junctions to prevent hemorrhage and aberrant angiogenesis.

KEYWORDS:

Angiogenesis; Mouse development; Retina; SMAD6; VE-cadherin

PMID:
30098998
DOI:
10.1016/j.ydbio.2018.07.027
[Indexed for MEDLINE]
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