Cyclic AMP-mobilizing agents and glucocorticoids modulate human smooth muscle cell migration.
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-alpha, 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-alpha, 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.
Goncharova
Elena A
EA
Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160, USA.
Billington
Charlotte K
CK
Irani
Carla
C
Vorotnikov
Alexander V
AV
Tkachuk
Vsevolod A
VA
Penn
Raymond B
RB
Krymskaya
Vera P
VP
Panettieri
Reynold A
RA
D000420:Albuterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D000068298:Fluticasone; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D008934:Mitogens / Q000494:pharmacology; D009130:Muscle, Smooth / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D020218:Response Elements / Q000187:drug effects / Q000235:genetics; D000068299:Salmeterol Xinafoate; D016211:Transforming Growth Factor alpha / Q000494:pharmacology
D000730:Androstadienes; D017362:Cyclic AMP Response Element-Binding Protein; D005938:Glucocorticoids; D008934:Mitogens; D010982:Platelet-Derived Growth Factor; D016211:Transforming Growth Factor alpha; D016222:Fibroblast Growth Factor 2; D000068299:Salmeterol Xinafoate; D003907:Dexamethasone; D000068298:Fluticasone; D000242:Cyclic AMP; D015232:Dinoprostone; D000420:Albuterol