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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:84.)
© 2005 American Heart Association, Inc.

Vascular Biology

Differential Effects of Vasodilatory Prostaglandins on Focal Adhesions, Cytoskeletal Architecture, and Migration in Human Aortic Smooth Muscle Cells

C. Bulin; U. Albrecht; J.G. Bode; A.-A. Weber; K. Schrör; B. Levkau; J.W. Fischer

From the Molekulare Pharmakologie (C.B., J.W.F.), Institut für Pharmakologie und Klinische Pharmakologie (A.-A.W., K.S.), Klinik für Gastroenterologie, Hepatologie und Infektiologie (U.A., J.G.B.), Heinrich Heine Universität Düsseldorf; and the Institut für Pathophysiologie, Universitätsklinikum Essen (B.L.), Germany.

Correspondence to Jens W. Fischer, Molecular Pharmacology, Institut für Pharmakologie and Klinische Pharmakologie, Heinrich-Heine-Universität Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf. E-mail jens.fischer{at}uni-duesseldorf.de

Objective— Cyclooxygenases 1 and 2 are expressed in atherosclerotic arteries, and local generation of prostacyclin and prostaglandin E₂ (PGE₂) occurs. However, the role of cyclooxygenases and individual prostaglandins during plaque progression is currently uncertain. The present study characterizes the effect of vasodilatory prostaglandins on morphology, focal adhesion (FA) function, and migration in human aortic smooth muscle cells (SMCs).

Methods and Results— The stable prostacyclin analog iloprost transiently induced: (1) disassembly of FA and stress fibers, (2) partial retraction and rounding of SMCs, (3) hypophosphorylation of FA kinase (FAK) and paxillin, and (4) inhibition of platelet-derived growth factor-BB–induced migration. Inhibition of FAK phosphorylation and morphological changes were mimicked by forskolin, inhibited by H89, and prevented by the protein tyrosine phosphatase inhibitor vanadate and by calpeptin. PGE₂ was by far less efficient with respect to all parameters investigated. This difference correlated with the respective cAMP induction in response to iloprost and PGE₂.

Conclusion— Inhibition of FAK phosphorylation and FA function is a new target of vasodilatory prostaglandins, which might be causally involved in the antimigratory effects of prostaglandins. Importantly, prostacyclin analogs and PGE₂ differ dramatically with respect to dephosphorylation of FAK and inhibition of migration, which might be of relevance for their respective functions in atherosclerosis.

The present study identifies focal adhesions (FAs) as a target of prostaglandin signaling in human vascular smooth muscle cells. Specifically, it is demonstrated that vasodilatory prostaglandins inhibit in a cAMP-dependent manner FA–kinase phosphorylation, which is associated with disassembly of FA, actin cytoskeleton, and reduced VSMC migration.

Key Words: focal adhesion kinase • extracellular matrix • prostaglandins • atherosclerosis

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