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J. Biol. Chem., Vol. 277, Issue 48, 45838-45846, November 29, 2002
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From the Centre Pluridisciplinaire d'Oncologie (CePO), University
of Lausanne Medical School, CH-1011 Lausanne, Switzerland
We have recently reported that the
inhibition of endothelial cell COX-2 by non-steroidal anti-inflammatory
drugs suppresses
Prostaglandin E2 Promotes Integrin
V
3-dependent Endothelial
Cell Adhesion, Rac-activation, and Spreading through
cAMP/PKA-dependent Signaling*
,
V
3- (but not
51-) dependent Rac activation,
endothelial cell spreading, migration, and angiogenesis (Dormond, O.,
Foletti, A., Paroz, C., and Ruegg, C. (2001) Nat. Med. 7, 1041-1047). Here we investigated the role of the COX-2 metabolites
PGE2 and TXA2 in regulating human umbilical vein
endothelial cell (HUVEC) adhesion and spreading. We report that
PGE2 accelerated V3-mediated
HUVEC adhesion and promoted Rac activation and cell spreading, whereas the TXA2 agonist U46619 retarded adhesion and inhibited spreading. We
show that the cAMP level and the cAMP-regulated protein kinase A (PKA)
activity are critical mediators of these PGE2 effects. V3-mediated adhesion induced a transient
COX-2-dependent rise in cAMP levels, whereas the
cell-permeable cAMP analogue 8-brcAMP accelerated adhesion, promoted
Rac activation, and cell spreading in the presence of the COX-2
inhibitor NS-398. Pharmacological inhibition of PKA completely blocked
V3-mediated adhesion. A constitutively
active Rac mutant (L61Rac) rescued
V3-dependent spreading in the
presence of NS398 or U46691, but did not accelerate adhesion, whereas a
dominant negative Rac mutant (N17Rac) suppressed spreading without
affecting adhesion. 51-mediated HUVEC
adhesion, Rac activation, and spreading were not affected by
PGE2, U46691, 8-brcAMP, or the inhibition of PKA. In
conclusion, these results demonstrate that PGE2 accelerates
V3-mediated endothelial cell adhesion
through cAMP-dependent PKA activation and induces
V3-dependent spreading via cAMP-
and PKA-dependent Rac activation and may contribute to the
further understanding of the regulation of vascular integrins V3 by COX-2/PGE2
during tumor angiogenesis and inflammation.
*
This work was supported by grants from the Swiss National
Science Foundation (31-52946.97 and 31-63752.00), the Leenaards Foundation, and the Banque Centonale Vaudoise (BCV) Foundation.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Recipient of an M.D./Ph.D. fellowship (31-51279.97) from the Swiss
National Science Foundation.
§
Recipient of a SCORE-A award (32-41611.94) from the Swiss National
Science Grant. To whom all correspondence should be addressed: Laboratory of the CePO, c/o Swiss Institute for Experimental Cancer Research (ISREC), 155 Chemin des Boveresses, CH-1066 Epalinges, Switzerland. Tel.: 41-21-692-5853; Fax: 41-21-692-5872; E-mail: curzio.ruegg@isrec.unil.ch.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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