PUBLICATION
Developmental SMAD6 Loss Leads to Blood Vessel Hemorrhage and Disrupted Endothelial Cell Junctions
- Authors
- Wylie, L.A., Mouillesseaux, K.P., Chong, D.C., Bautch, V.L.
- ID
- ZDB-PUB-180814-6
- Date
- 2018
- Source
- Developmental Biology 442(2): 199-209 (Journal)
- Registered Authors
- Chong, Diana, Mouillesseaux, Kevin
- Keywords
- SMAD6, VE-cadherin, angiogenesis, mouse development, retina
- MeSH Terms
-
- Adherens Junctions/metabolism
- Animals
- Arteries/metabolism
- Blood Vessels/metabolism
- Blood Vessels/physiology*
- Endothelial Cells/physiology
- Endothelium, Vascular/metabolism
- Hemorrhage/blood
- Intercellular Junctions/physiology
- Mice
- Neovascularization, Pathologic/genetics
- Neovascularization, Physiologic/genetics
- Retinal Vessels
- Signal Transduction
- Smad6 Protein/genetics*
- Smad6 Protein/physiology*
- PubMed
- 30098998 Full text @ Dev. Biol.
Citation
Wylie, L.A., Mouillesseaux, K.P., Chong, D.C., Bautch, V.L. (2018) Developmental SMAD6 Loss Leads to Blood Vessel Hemorrhage and Disrupted Endothelial Cell Junctions. Developmental Biology. 442(2):199-209.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping