PUBLICATION
Plasminogen Activator Inhibitor-1 Controls Vascular Integrity by Regulating VE-Cadherin Trafficking
- Authors
- Daniel, A.E., Timmerman, I., Kovacevic, I., Hordijk, P.L., Adriaanse, L., Paatero, I., Belting, H.G., van Buul, J.D.
- ID
- ZDB-PUB-151230-1
- Date
- 2015
- Source
- PLoS One 10: e0145684 (Journal)
- Registered Authors
- Belting, Heinz-Georg Paul (Henry)
- Keywords
- Endothelial cells, Zebrafish, Fluorescence recovery after photobleaching, Embryos, Vascular permeability, Catenins, Immunoprecipitation, Golgi apparatus
- MeSH Terms
-
- Cadherins/metabolism*
- Plasminogen Activator Inhibitor 1/metabolism*
- Human Umbilical Vein Endothelial Cells/cytology
- Human Umbilical Vein Endothelial Cells/drug effects
- Human Umbilical Vein Endothelial Cells/metabolism
- Zebrafish
- Protein Transport/drug effects
- Endothelium, Vascular/drug effects
- Endothelium, Vascular/metabolism*
- Humans
- Intercellular Junctions/drug effects
- Animals
- Indoleacetic Acids/pharmacology
- PubMed
- 26714278 Full text @ PLoS One
Citation
Daniel, A.E., Timmerman, I., Kovacevic, I., Hordijk, P.L., Adriaanse, L., Paatero, I., Belting, H.G., van Buul, J.D. (2015) Plasminogen Activator Inhibitor-1 Controls Vascular Integrity by Regulating VE-Cadherin Trafficking. PLoS One. 10:e0145684.
Abstract
Background Plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor, is expressed and secreted by endothelial cells. Patients with PAI-1 deficiency show a mild to moderate bleeding diathesis, which has been exclusively ascribed to the function of PAI-1 in down-regulating fibrinolysis. We tested the hypothesis that PAI-1 function plays a direct role in controlling vascular integrity and permeability by keeping endothelial cell-cell junctions intact.
Methodology/principal findings We utilized PAI-039, a specific small molecule inhibitor of PAI-1, to investigate the role of PAI-1 in protecting endothelial integrity. In vivo inhibition of PAI-1 resulted in vascular leakage from intersegmental vessels and in the hindbrain of zebrafish embryos. In addition PAI-1 inhibition in human umbilical vein endothelial cell (HUVEC) monolayers leads to a marked decrease of transendothelial resistance and disrupted endothelial junctions. The total level of the endothelial junction regulator VE-cadherin was reduced, whereas surface VE-cadherin expression was unaltered. Moreover, PAI-1 inhibition reduced the shedding of VE-cadherin. Finally, we detected an accumulation of VE-cadherin at the Golgi apparatus.
Conclusions/significance Our findings indicate that PAI-1 function is important for the maintenance of endothelial monolayer and vascular integrity by controlling VE-cadherin trafficking to and from the plasma membrane. Our data further suggest that therapies using PAI-1 antagonists like PAI-039 ought to be used with caution to avoid disruption of the vessel wall.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping