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First published online 12 February 2003
doi: 10.1242/jcs.00308
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Research Article |
1 Institute of Signaling, Developmental Biology and Cancer Research, CNRS-UMR
6543, Centre Antoine Lacassagne, 33 Avenue de Valombrose, 06189 Nice,
France
2 Rammelkamp Center for Research, R421 and Department of Pharmacology and
Ireland Cancer Center, Case Western Reserve University School of Medicine,
2500 MetroHealth Drive, Cleveland, OH 44109, USA
* Present address: Laboratory of Connective Tissues Biology, University of
Liège, Tour de Pathologie, B23/3, 4000 Liège, Sart Tilman,
Belgium
Author for correspondence (e-mail:
c.deroanne{at}ulg.ac.be)
Accepted 5 December 2002
Interactions between the Eph receptor tyrosine kinase and ephrin ligands transduce short-range signals regulating axon pathfinding, development of the cardiovascular system, as well as migration and spreading of neuronal and non-neuronal cells. Some of these effects are believed to be mediated by alterations in actin dynamics. The members of the small Rho GTPase family elicit various effects on actin structures and are probably involved in Eph receptor-induced actin modulation. EphrinA1 is proposed to contribute to angiogenesis as it is strongly expressed at sites of neovascularization. Moreover, angiogenic factors induce the expression of ephrinA1 in endothelial cells. In this study, using rat vascular smooth muscle cells (VSMCs), we investigated the contribution of the small Rho GTPases in ephrinA1-induced integrin inactivation. EphrinA1 did not significantly affect early adhesion of VSMCs on purified laminin or fibronectin, but strongly impaired cell spreading. The Rho kinase inhibitor Y-27632 partly reversed the ephrinA1 effect, suggesting involvement of Rho in this model. However, inhibition of RhoA synthesis with short interfering (si)RNA had a modest effect, suggesting that RhoA plays a limited role in ephrinA1-mediated inhibition of spreading in VSMCs. The ephrinA1-mediated morphological alterations correlated with inhibition of Rac1 and p21-activated kinase 1 (PAK1) activity, and were antagonized by the expression of a constitutively active Rac mutant. Moreover, repression of Rac1 synthesis with siRNA amplifies the ephrinA1-induced inhibition of spreading. Finally, sphingosine-1-phosphate (S1P), a lipid mediator known to inhibit Rac activation in VSMCs amplifies the ephrinA1 effect. In conclusion, our results emphasize the role of the Rac/PAK pathway in ephrinA1-mediated inhibition of spreading. In this way, ephrinA1, alone or in synergy with S1P, can participate in blood vessel destabilization, a prerequisite for angiogenesis.
Key words: EphrinA1, RhoGTPases, siRNA, Lamellipodia, Integrin, Laminin
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