Hepatocyte growth factor enhances endothelial cell barrier function and cortical cytoskeletal rearrangement: Potential role of glycogen synthase kinase-3β

Feng Liu, Kane L. Schaphorst, Alexander Dmitriyevich Verin, Keri Jacobs, Anna Birukova, Regina M. Day, Natalia Bogatcheva, D. P. Bottaro, Joe G.N. Garcia

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

The stabilization of endothelial cell (EC) barrier function within newly formed capillaries is a critical feature of angiogenesis. We examined human lung EC barrier regulation elicited by hepatocyte growth factor (HGF), a recognized angiogenic factor and EC chemoattractant. HGF rapidly and dose-dependently elevated transendothelial electrical resistance (TER) of EC monolayers (>50% increase at 100 ng/ml), with immunofluorescence microscopic evidence of both cytoplasmic actin stress fiber dissolution and strong augmentation of the cortical actin ring. HGF rapidly stimulated phosphatidylinositol 3′-kinase, ERK, p38 mitogen-activated protein kinase, and protein kinase C activities. Pharmacological inhibitor studies demonstrated each pathway to be intimately involved in HGF-induced increases in TER, cortical actin thickening, and phosphorylation of the Ser/Thr glycogen synthase kinase-3β (GSK-3β), a potential target for the HGF barrier-promoting response. GSK-3β phosphorylation was strongly correlated with reductions in both HGF-induced TER and enhanced β-catenin immunoreactivity observed at cell-cell junctions. Our data suggest a model in which HGF-mediated EC cytoskeletal rearrangement and barrier enhancement depend critically on the activation of a complex kinase cascade that converges at GSK-3β to increase the availability of β-catenin, thereby enhancing endothelial junctional integrity and vascular barrier function.-Liu, F., Schaphorst, K. L., Verin, A. D., Jacobs, K., Birukova, A., Day, R. M., Bogatcheva, N., Bottaro, D. P., Garcia, J. G. N. Hepatocyte growth factor enhances endothelial cell barrier function and cortical cytoskeletal rearrangement: potential role of glycogen synthase kinase-3β.

Original languageEnglish (US)
Pages (from-to)950-962
Number of pages13
JournalFASEB Journal
Volume16
Issue number9
DOIs
StatePublished - Jul 22 2002
Externally publishedYes

Fingerprint

Glycogen Synthase Kinase 3
Hepatocyte Growth Factor
Endothelial cells
Endothelial Cells
Acoustic impedance
Electric Impedance
Actins
Catenins
Phosphorylation
p38 Mitogen-Activated Protein Kinases
Phosphatidylinositol 3-Kinase
Stress Fibers
Intercellular Junctions
Angiogenesis Inducing Agents
Chemotactic Factors
Mitogen-Activated Protein Kinase Kinases
Protein Kinase C
Fluorescent Antibody Technique
Blood Vessels
Monolayers

Keywords

  • Cytoskeleton
  • Endothelial permeability
  • MAP kinases
  • Transendothelial electrical resistance
  • β-Catenin

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Hepatocyte growth factor enhances endothelial cell barrier function and cortical cytoskeletal rearrangement : Potential role of glycogen synthase kinase-3β. / Liu, Feng; Schaphorst, Kane L.; Verin, Alexander Dmitriyevich; Jacobs, Keri; Birukova, Anna; Day, Regina M.; Bogatcheva, Natalia; Bottaro, D. P.; Garcia, Joe G.N.

In: FASEB Journal, Vol. 16, No. 9, 22.07.2002, p. 950-962.

Research output: Contribution to journalArticle

Liu, Feng ; Schaphorst, Kane L. ; Verin, Alexander Dmitriyevich ; Jacobs, Keri ; Birukova, Anna ; Day, Regina M. ; Bogatcheva, Natalia ; Bottaro, D. P. ; Garcia, Joe G.N. / Hepatocyte growth factor enhances endothelial cell barrier function and cortical cytoskeletal rearrangement : Potential role of glycogen synthase kinase-3β. In: FASEB Journal. 2002 ; Vol. 16, No. 9. pp. 950-962.
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T1 - Hepatocyte growth factor enhances endothelial cell barrier function and cortical cytoskeletal rearrangement

T2 - Potential role of glycogen synthase kinase-3β

AU - Liu, Feng

AU - Schaphorst, Kane L.

AU - Verin, Alexander Dmitriyevich

AU - Jacobs, Keri

AU - Birukova, Anna

AU - Day, Regina M.

AU - Bogatcheva, Natalia

AU - Bottaro, D. P.

AU - Garcia, Joe G.N.

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N2 - The stabilization of endothelial cell (EC) barrier function within newly formed capillaries is a critical feature of angiogenesis. We examined human lung EC barrier regulation elicited by hepatocyte growth factor (HGF), a recognized angiogenic factor and EC chemoattractant. HGF rapidly and dose-dependently elevated transendothelial electrical resistance (TER) of EC monolayers (>50% increase at 100 ng/ml), with immunofluorescence microscopic evidence of both cytoplasmic actin stress fiber dissolution and strong augmentation of the cortical actin ring. HGF rapidly stimulated phosphatidylinositol 3′-kinase, ERK, p38 mitogen-activated protein kinase, and protein kinase C activities. Pharmacological inhibitor studies demonstrated each pathway to be intimately involved in HGF-induced increases in TER, cortical actin thickening, and phosphorylation of the Ser/Thr glycogen synthase kinase-3β (GSK-3β), a potential target for the HGF barrier-promoting response. GSK-3β phosphorylation was strongly correlated with reductions in both HGF-induced TER and enhanced β-catenin immunoreactivity observed at cell-cell junctions. Our data suggest a model in which HGF-mediated EC cytoskeletal rearrangement and barrier enhancement depend critically on the activation of a complex kinase cascade that converges at GSK-3β to increase the availability of β-catenin, thereby enhancing endothelial junctional integrity and vascular barrier function.-Liu, F., Schaphorst, K. L., Verin, A. D., Jacobs, K., Birukova, A., Day, R. M., Bogatcheva, N., Bottaro, D. P., Garcia, J. G. N. Hepatocyte growth factor enhances endothelial cell barrier function and cortical cytoskeletal rearrangement: potential role of glycogen synthase kinase-3β.

AB - The stabilization of endothelial cell (EC) barrier function within newly formed capillaries is a critical feature of angiogenesis. We examined human lung EC barrier regulation elicited by hepatocyte growth factor (HGF), a recognized angiogenic factor and EC chemoattractant. HGF rapidly and dose-dependently elevated transendothelial electrical resistance (TER) of EC monolayers (>50% increase at 100 ng/ml), with immunofluorescence microscopic evidence of both cytoplasmic actin stress fiber dissolution and strong augmentation of the cortical actin ring. HGF rapidly stimulated phosphatidylinositol 3′-kinase, ERK, p38 mitogen-activated protein kinase, and protein kinase C activities. Pharmacological inhibitor studies demonstrated each pathway to be intimately involved in HGF-induced increases in TER, cortical actin thickening, and phosphorylation of the Ser/Thr glycogen synthase kinase-3β (GSK-3β), a potential target for the HGF barrier-promoting response. GSK-3β phosphorylation was strongly correlated with reductions in both HGF-induced TER and enhanced β-catenin immunoreactivity observed at cell-cell junctions. Our data suggest a model in which HGF-mediated EC cytoskeletal rearrangement and barrier enhancement depend critically on the activation of a complex kinase cascade that converges at GSK-3β to increase the availability of β-catenin, thereby enhancing endothelial junctional integrity and vascular barrier function.-Liu, F., Schaphorst, K. L., Verin, A. D., Jacobs, K., Birukova, A., Day, R. M., Bogatcheva, N., Bottaro, D. P., Garcia, J. G. N. Hepatocyte growth factor enhances endothelial cell barrier function and cortical cytoskeletal rearrangement: potential role of glycogen synthase kinase-3β.

KW - Cytoskeleton

KW - Endothelial permeability

KW - MAP kinases

KW - Transendothelial electrical resistance

KW - β-Catenin

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