Journal
JOURNAL OF CELLULAR PHYSIOLOGY
Volume 208, Issue 3, Pages 495-505Publisher
WILEY-LISS
DOI: 10.1002/jcp.20673
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Transition of vascular smooth muscle cells from a contractile/quiescent to a secretory/proliferative phenotype is one of the critical steps in atherosclerosis and is instigated by pro-inflammatory cytokines released from macrophages that have infiltrated into the vascular wall. In most inflammatory diseases, cell activation induced by these compounds leads to a massive production of type E-2 prostaglandin (PGE(2)) which often takes over and even potentiates the pro-inflammatory cytokine-related effects. To evaluate PGE(2) incidence on atheroma plaque development, we investigated whether and how this compound could enhance the dedifferentiation of smooth muscle cells initially induced by interleukin-1 beta (IL-1 beta). To address this issue, we took advantage of vascular smooth muscle cells in primary culture and tracked two markers: PLA(2) secretion and alpha-actin filament disorganization. In such a context, we found that PGE(2) synergizes with IL-1 beta to further enhance the phenotype transition of smooth muscle cells, through cAMP-protein kinase A. As indicated by pharmacological studies, the full PGE(2)-dependent potentiation of IL-1 beta induced PLA(2) secretion is associated with a change of regulation exerted by the subtypes 3 G(i)-coupled PGE2 receptors toward adenylyl cyclase(s) activated by the subtype 4 G(s)-linked PGE(2) receptor. Whereas on contractile cells, stimulated subtypes 3 inhibit type 4-dependent PLA(2) secretion, this negative regulation is switched to positive on IL-1 beta-treated cells. Using real time PCR, pharmacological tools and small interfering RNA (siRNA), we demonstrated that the different integration of PGE(2) signals depends on the upregulation of calcium/calmodulin stimulable adenylyl cyclase 8.
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