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Prostacyclin Induces Apoptosis of Vascular Smooth Muscle Cells by a cAMP-Mediated Inhibition of Extracellular Signal-Regulated Kinase Activity and Can Counteract the Mitogenic Activity of Endothelin-1 or Basic Fibroblast Growth Factor

From the Babraham Institute (R.-c.L., L.A.S.), Babraham, Cambridge, UK; the Department of Anatomy (T.C.-D.), and the Multi-Imaging Centre (J.N.S.), University of Cambridge, Cambridge, UK.

Correspondence to Lynda A. Sellers, Babraham Institute, Babraham, Cambridge, CB2 4AT, UK. E-mail lynda.sellers{at}bbsrc.ac.uk

Prostanoids can suppress vascular smooth muscle cell (VSMC) proliferation, but the mechanism through which this is mediated has not been identified. In this study, we show rat aortic VSMCs to express the EP₁, EP₂, EP₃, EP₄, and IP receptors. The EP₄ receptor–specific agonist, 11-deoxy-PGE₁, induced a time-dependent phosphorylation of protein kinase C and extracellular signal-regulated kinase (ERK) 1/2 in serum-depleted (0.1%) VSMCs, whereas the EP₂ receptor agonist, butaprost, was without effect. PGI₂ or iloprost at the IP receptor inhibited basal ERK phosphorylation with IC₅₀ values of 10 nmol/L. Iloprost also attenuated the sustained activation of ERK induced by endothelin-1 or basic fibroblast growth factor (bFGF). Endothelin-1 or bFGF significantly increased the number of VSMCs counted 24 hours later compared with basal, and both responses were blocked by the MEK inhibitor, U0126, or iloprost. Under basal conditions, U0126 or iloprost reduced the number of viable cells and increased caspase-3 activity, which could be reversed by coapplication with endothelin-1, bFGF, or the adenylate cyclase inhibitor, SQ22536. Endothelin-1, bFGF, or SQ22536 prevented the depression to below basal levels of ERK phosphorylation induced by iloprost. Forskolin activated caspase-3 and attenuated basal ERK phosphorylation, which were prevented by SQ22536, endothelin-1, or bFGF. These data suggest that iloprost induces apoptosis via a cAMP-mediated suppression of ERK activity. In turn, this apoptotic response can be blocked by a mitogenic stimulus that re-establishes ERK activity back to basal levels, but at the expense of any concomitant proliferative activity. However, ERK stimulation by a selective EP₄ receptor agonist, suggests that prostanoids may have diverse and complex roles in VSMC physiology.

Key Words: prostacyclin • apoptosis • vascular smooth muscle cells • endothelin • mitogen-activated protein kinase

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