on December 26, 2002
Arteriosclerosis, Thrombosis, and Vascular Biology. 2002
Published online before print December 26, 2002, doi: 10.1161/01.ATV.0000054198.68894.88
Published online before print December 26, 2002, doi: 10.1161/01.ATV.0000054198.68894.88
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Submitted on October 7, 2002
Accepted on November 25, 2002
Involvement of RhoA/Rho Kinase Signaling in VEGF-Induced Endothelial Cell Migration and Angiogenesis In Vitro
Geerten P. van Nieuw Amerongen ;
From the Laboratory for Physiology (G.P.v.N.A., V.W.M.v.H.), Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, and the Gaubius Laboratory TNO-PG (P.K., A.V., V.W.M.v.H.), Leiden, the Netherlands.
* To whom correspondence should be addressed. E-mail: vwm.vanhinsbergh{at}pg.tno.nl.
Objective—Growth factor-induced angiogenesis involves migration of endothelial cells (ECs) into perivascular areas and requires active remodeling of the endothelial F-actin cytoskeleton. The small GTPase RhoA previously has been implicated in vascular endothelial growth factor (VEGF)-induced signaling pathways, but its role has not been clarified.
Methods and Results—VEGF induced the activation of RhoA and recruited RhoA to the cell membrane of human ECs. This increase in RhoA activity is necessary for the VEGF-induced reorganization of the F-actin cytoskeleton, as demonstrated by adenoviral transfection of dominant-negative RhoA. Rho kinase mediated this effect of RhoA, as was demonstrated by the use of Y-27632, a specific inhibitor of Rho kinase. Inhibition of Rho kinase prevented the VEGF-enhanced EC migration in response to mechanical wounding but had no effect on basal EC migration. Furthermore, in an in vitro model for angiogenesis, inhibition of either RhoA or Rho kinase attenuated the VEGF-mediated ingrowth of ECs in a 3-dimensional fibrin matrix.
Conclusions—VEGF-induced cytoskeletal changes in ECs require RhoA and Rho kinase, and activation of RhoA/Rho kinase signaling is involved in the VEGF-induced in vitro EC migration and angiogenesis.
Key words: endothelial cells • migration • angiogenesis • cytoskeleton • stress fibers
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