PUBLICATION
Role of ADTRP (Androgen-Dependent Tissue Factor Pathway Inhibitor Regulating Protein) in Vascular Development and Function
- Authors
- Patel, M.M., Behar, A.R., Silasi, R., Regmi, G., Sansam, C.L., Keshari, R.S., Lupu, F., Lupu, C.
- ID
- ZDB-PUB-181221-11
- Date
- 2018
- Source
- Journal of the American Heart Association 7: e010690 (Journal)
- Registered Authors
- Keywords
- vascular inflammation, vascular permeability, vascular stability, Wnt signaling, vascular function, vasculopathy
- MeSH Terms
-
- Animals
- Animals, Newborn/growth & development
- Blood Vessels/embryology
- Blood Vessels/growth & development*
- Blotting, Western
- Female
- Fluorescent Antibody Technique
- Gene Knockout Techniques
- Lipoproteins/physiology*
- Male
- Mice
- Mice, Inbred C57BL
- Microscopy, Electron, Transmission
- Real-Time Polymerase Chain Reaction
- Zebrafish/embryology
- Zebrafish/growth & development
- PubMed
- 30571485 Full text @ J. Am. Heart Assoc.
Citation
Patel, M.M., Behar, A.R., Silasi, R., Regmi, G., Sansam, C.L., Keshari, R.S., Lupu, F., Lupu, C. (2018) Role of ADTRP (Androgen-Dependent Tissue Factor Pathway Inhibitor Regulating Protein) in Vascular Development and Function. Journal of the American Heart Association. 7:e010690.
Abstract
Background The physiological function of ADTRP (androgen-dependent tissue factor pathway inhibitor regulating protein) is unknown. We previously identified ADTRP as coregulating with and supporting the anticoagulant activity of tissue factor pathway inhibitor in endothelial cells in vitro. Here, we studied the role of ADTRP in vivo, specifically related to vascular development, stability, and function. Methods and Results Genetic inhibition of Adtrp produced vascular malformations in the low-pressure vasculature of zebrafish embryos and newborn mice: dilation/tortuosity, perivascular inflammation, extravascular proteolysis, increased permeability, and microhemorrhages, which produced partially penetrant lethality. Vascular leakiness correlated with decreased endothelial cell junction components VE -cadherin and claudin-5. Changes in hemostasis in young adults comprised modest decrease of tissue factor pathway inhibitor antigen and activity and increased tail bleeding time and volume. Cell-based reporter assays revealed that ADTRP negatively regulates canonical Wnt signaling, affecting membrane events downstream of low-density lipoprotein receptor-related protein 6 ( LRP 6) and upstream of glycogen synthase kinase 3 beta. ADTRP deficiency increased aberrant/ectopic Wnt/β-catenin signaling in vivo in newborn mice and zebrafish embryos, and upregulated matrix metallopeptidase ( MMP )-9 in endothelial cells and mast cells ( MCs ). Vascular lesions in newborn Adtrp -/- pups displayed accumulation of MCs , decreased extracellular matrix content, and deficient perivascular cell coverage. Wnt-pathway inhibition reversed the increased mmp9 in zebrafish embryos, demonstrating that mmp9 expression induced by Adtrp deficiency was downstream of canonical Wnt signaling. Conclusions Our studies demonstrate that ADTRP plays a major role in vascular development and function, most likely through expression in endothelial cells and/or perivascular cells of Wnt-regulated genes that control vascular stability and integrity.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping