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 VEcadherin. 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.
| Original language | English |
|---|---|
| Article number | e0145684 |
| Journal | PLoS ONE |
| Volume | 10 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - 1 Dec 2015 |
Cite this
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Plasminogen activator inhibitor-1 controls vascular integrity by regulating VE-cadherin trafficking. / Daniel, Anna E.; Timmerman, Ilse; Kovacevic, Igor; Hordijk, Peter L.; Adriaanse, Luc; Paatero, Ilkka; Belting, Heinz Georg; Van Buul, Jaap D.
In: PLoS ONE, Vol. 10, No. 12, e0145684, 01.12.2015.Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Plasminogen activator inhibitor-1 controls vascular integrity by regulating VE-cadherin trafficking
AU - Daniel, Anna E.
AU - Timmerman, Ilse
AU - Kovacevic, Igor
AU - Hordijk, Peter L.
AU - Adriaanse, Luc
AU - Paatero, Ilkka
AU - Belting, Heinz Georg
AU - Van Buul, Jaap D.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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 VEcadherin. 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.
AB - 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 VEcadherin. 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.
UR - http://www.scopus.com/inward/record.url?scp=84957562827&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0145684
DO - 10.1371/journal.pone.0145684
M3 - Article
VL - 10
JO - PLoS ONE
JF - PLoS ONE
SN - 1932-6203
IS - 12
M1 - e0145684
ER -