TY - JOUR
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 D.
AU - Jacobs, Keri
AU - Birukova, Anna
AU - Day, Regina M.
AU - Bogatcheva, Natalia
AU - Bottaro, D. P.
AU - Garcia, Joe G.N.
PY - 2002
Y1 - 2002
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
UR - http://www.scopus.com/inward/record.url?scp=0036315009&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036315009&partnerID=8YFLogxK
U2 - 10.1096/fj.01-0870com
DO - 10.1096/fj.01-0870com
M3 - Article
C2 - 12087056
AN - SCOPUS:0036315009
SN - 0892-6638
VL - 16
SP - 950
EP - 962
JO - FASEB Journal
JF - FASEB Journal
IS - 9
ER -