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*Centre de Biochimie, Centre National de la Recherche Scientifique,
UMR 6543, 06108 Nice Cedex 2, France; and
Endothelial barrier function is regulated at the cellular level by
cytoskeletal-dependent anchoring and retracting forces. In the present
study we have examined the signal transduction pathways underlying
agonist-stimulated reorganization of the actin cytoskeleton in human
umbilical vein endothelial cells. Receptor activation by thrombin, or
the thrombin receptor (proteinase-activated receptor 1) agonist
peptide, leads to an early increase in stress fiber formation followed
by cortical actin accumulation and cell rounding. Selective inhibition
of thrombin-stimulated signaling systems, including Gi/o (pertussis
toxin sensitive), p42/p44, and p38 MAP kinase cascades, Src family
kinases, PI-3 kinase, or S6 kinase pathways had no effect on the
thrombin response. In contrast, staurosporine and KT5926, an inhibitor
of myosin light chain kinase, effectively blocked thrombin-induced cell rounding and retraction. The contribution of Rho to these effects was
analyzed by using bacterial toxins that either activate or inhibit the
GTPase. Escherichia coli cytotoxic necrotizing factor 1, an activator of Rho, induced the appearance of dense actin cables
across cells without perturbing monolayer integrity. Accordingly, lysophosphatidic acid, an activator of Rho-dependent stress fiber formation in fibroblasts, led to reorganization of polymerized actin
into stress fibers but failed to induce cell rounding. Inhibition of
Rho with Clostridium botulinum exoenzyme C3 fused to the
B fragment of diphtheria toxin caused loss of stress fibers with only
partial attenuation of thrombin-induced cell rounding. The implication
of Rac and Cdc42 was analyzed in transient transfection experiments
using either constitutively active (V12) or dominant-interfering (N17)
mutants. Expression of RacV12 mimicked the effect of thrombin on cell
rounding, and RacN17 blocked the response to thrombin, whereas Cdc42
mutants were without effect. These observations suggest that Rho is
involved in the maintenance of endothelial barrier function and Rac
participates in cytoskeletal remodeling by thrombin in human umbilical
vein endothelial cells.
Institut
National de la Santé et de la Recherche Médicale, U452
Faculté de Médecine de Nice, 06107 Nice Cedex 2, France
Corresponding author. E-mail address:
vanobber{at}unice.fr.
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