Plasminogen activator inhibitor-1 controls vascular integrity by regulating VE-cadherin trafficking

Anna E. Daniel, Ilse Timmerman, Igor Kovacevic, Peter L. Hordijk, Luc Adriaanse, Ilkka Paatero, Heinz Georg Belting, Jaap D. Van Buul

Research output: Contribution to journalArticleAcademicpeer-review

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 languageEnglish
Article numbere0145684
JournalPLoS ONE
Volume10
Issue number12
DOIs
Publication statusPublished - 1 Dec 2015

Cite this

Daniel, Anna E. ; Timmerman, Ilse ; Kovacevic, Igor ; Hordijk, Peter L. ; Adriaanse, Luc ; Paatero, Ilkka ; Belting, Heinz Georg ; Van Buul, Jaap D. / Plasminogen activator inhibitor-1 controls vascular integrity by regulating VE-cadherin trafficking. In: PLoS ONE. 2015 ; Vol. 10, No. 12.
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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.",
author = "Daniel, {Anna E.} and Ilse Timmerman and Igor Kovacevic and Hordijk, {Peter L.} and Luc Adriaanse and Ilkka Paatero and Belting, {Heinz Georg} and {Van Buul}, {Jaap D.}",
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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 journalArticleAcademicpeer-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.

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