Differential effects of vasodilatory prostaglandins on focal adhesions, cytoskeletal architecture, and migration in human aortic smooth muscle cells.
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).


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.


CONCLUSIONS
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.
Molecular Pharmacology, Heinrich Heine Universität Düsseldorf, Germany.
C
C
Bulin
U
U
Albrecht
J G
JG
Bode
A-A
AA
Weber
K
K
Schrör
B
B
Levkau
J W
JW
Fischer
D000199:Actins / Q000378:metabolism; D001011:Aorta / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D003599:Cytoskeleton / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D022001:Focal Adhesions / Q000378:metabolism*; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular; D032389:Myocytes, Smooth Muscle; D010766:Phosphorylation; D011453:Prostaglandins / Q000378:metabolism* / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D044006:Receptors, Epoprostenol / Q000096:biosynthesis; D011982:Receptors, Prostaglandin / Q000502:physiology; D018078:Receptors, Prostaglandin E / Q000096:biosynthesis; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D014664:Vasodilation / Q000502:physiology*
D000199:Actins; C545635:PTGER1 protein, human; C545644:PTGER2 protein, human; C113936:PTGIR protein, human; D011453:Prostaglandins; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D016285:Iloprost; D015232:Dinoprostone