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

Elena A. Goncharova, Charlotte K. Billington, Carla Irani, Alexander V. Vorotnikov, Vsevolod A. Tkachuk, Raymond B. Penn, Vera P. Krymskaya, Reynold A. Panettieri
2003 American Journal of Respiratory Cell and Molecular Biology  
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
more » ... antly 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 E 2 , salmeterol, and the phosphodiesterase type 4 inhibitor cilomolast inhibited basal ASM and PVSM migration by 30-60%. Prostaglandin E 2 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 cAMPmobilizing agents and steroids modulate human smooth muscle cell migration, likely by distinct mechanisms. Increased smooth muscle mass is frequently associated with diseases manifested by increased airway or pulmonary vascular resistance (1-3). Growth factors, contractile agonists, and inflammatory mediators stimulate abnormal smooth (
doi:10.1165/rcmb.2002-0254oc pmid:12600820 fatcat:tuoyywhqingpdgsi6q6o4gygoe