Activation of IP and EP(3) receptors alters cAMP-dependent cell migration.
Migration of vascular smooth cells from the media to the intima essentially contributes to neointima formation after percutaneous transluminal angioplasty and stent implantation. The stable prostacyclin mimetic iloprost has been shown to inhibit neointima formation in experimental restenosis, but it is currently unknown whether this may be caused by an antimigratory effect. Hence, the present study analyses (i) the influence of G(s)-coupled prostacyclin (IP) receptors on cell migration and (ii) verifies whether EP(3) receptors with opposite (i.e., G(i)) coupling may conversely stimulate cell migration. In a modified Boyden chamber model, it was shown that iloprost dose-dependently inhibits the migration of primary human arterial smooth muscle cells, which constitutively express the IP receptor. On the other hand, human arterial smooth muscle cell migration was stimulated by the EP(3) receptor agonist M&B 28.767. To independently study the effects of these receptors, IP or EP(3) receptors were stably overexpressed in chinese hamster ovary cells (CHO-IP and CHO-EP(3)). Chemotaxis of CHO cells transfected with G(s)-coupled IP receptors was concentration-dependently inhibited by iloprost (2-100 nM), while there was no effect of iloprost on mock-transfected CHO. By contrast, CHO-cells that overexpressed EP(3) receptors showed a significant, concentration dependent (1-100 nM) increase of cell migration in presence of the selective EP(3) agonist M&B 28.767. It is concluded that the prostacyclin mimetic iloprost inhibits vascular cell migration, which probably depends on a G(s)-mediated increase of intracellular cAMP. EP(3) receptors conversely stimulate CHO migration.
Medical Clinic I, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany. ruediger.blindt@post.rwth-aachen.de
Rüdiger
R
Blindt
Anja-K
AK
Bosserhoff
Jürgen
J
vom Dahl
Peter
P
Hanrath
Karsten
K
Schrör
Thomas
T
Hohlfeld
Jutta
J
Meyer-Kirchrath
D000818:Animals; D016466:CHO Cells; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D006224:Cricetinae; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000378:metabolism*; D006801:Humans; D016285:Iloprost / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D018078:Receptors, Prostaglandin E / Q000187:drug effects*; D058308:Receptors, Prostaglandin E, EP3 Subtype
C545647:PTGER3 protein, human; C113936:PTGIR protein, human; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; C034220:cyclic adenosine-5'-trimetaphosphate; D000242:Cyclic AMP; D016285:Iloprost