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Cyclic AMP-Mobilizing Agents and Glucocorticoids Modulate Human Smooth Muscle Cell Migration

Pulmonary, Allergy, and Critical Care Division, Department of Medicine, University of Pennsylvania; Division of Critical Care, Pulmonary, Allergic & Immunologic Diseases, Jefferson Medical College, and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania; and Laboratory of Cell Motility, Laboratory of Molecular Endocrinology, Institute of Experimental Cardiology, Russian Cardiology Research Center, Moscow, Russia

Address correspondence to: Reynold A. Panettieri, Jr., M.D., Pulmonary, Allergy and Critical Care Division, University of Pennsylvania, 421 Curie Boulevard, Room 805 BRB II/III, Philadelphia, PA 19104-6160. E-mail: rap{at}mail.med.upenn.edu

Hyperplasia and cell migration of smooth muscle are features of both airway and pulmonary vascular diseases. The precise cellular and molecular mechanisms that regulate smooth muscle migration in the lungs remain unknown. In this study, we examined the effect of cAMP-mobilizing agents and steroids on smooth muscle cell migration. Platelet-derived growth factor (PDGF), transforming growth factor-, vascular endothelial growth factor, and basic fibroblast growth factor significantly stimulated cell migration in pulmonary vascular smooth muscle (PVSM) cells. Airway smooth muscle (ASM) migration was also stimulated by PDGF, transforming growth factor-, and basic fibroblast growth factor, but vascular endothelial growth factor was without effect. Interestingly, the smooth muscle mitogen thrombin did not stimulate migration of either cell type. Agents capable of elevating intracellular cAMP inhibited basal (unstimulated) cell migration in both cell types, whereas their effects on PDGF-stimulated migration were more variable. Prostaglandin E₂, salmeterol, and the phosphodiesterase type 4 inhibitor cilomolast inhibited basal ASM and PVSM migration by 30–60%. Prostaglandin E₂ and cilomolast also inhibited PDGF-stimulated migration of ASM and PVSM cells, but salmeterol was without effect. Preincubation of ASM cells with dexamethasone or fluticasone inhibited basal and PDGF-stimulated migration, and enabled an inhibitory effect of salmeterol on PDGF-induced cell migration. Steroids alone did not stimulate cAMP production or cAMP/PKA-dependent gene transcription (CRE-Luc activity), but slightly augmented salmeterol-stimulated CRE-Luc activity. Collectively, these findings demonstrate that cAMP-mobilizing agents and steroids modulate human smooth muscle cell migration, likely by distinct mechanisms.

Abbreviations: airway smooth muscle, ASM • basic fibroblast growth factor, bFGF • cAMP/PKA-dependent gene transcription, CRE-Luc activity • fetal bovine serum, FBS • phosphodiesterase type 4, PDE4 • platelet-derived growth factor, PDGF • prostaglandin E₂, PGE₂ • pulmonary vascular smooth muscle, PVSM • transforming growth factor-, TGF- • vascular endothelial growth factor, VEGF