β₂-Adrenergic Receptor Agonists Modulate Human Airway Smooth Muscle Cell Migration via Vasodilator-Stimulated Phosphoprotein

Abstract

Severe asthma manifests as airway remodeling and irreversible airway obstruction, in part because of the proliferation and migration of human airway smooth muscle (HASM) cells. We previously reported that cyclic adenosine monophosphate-mobilizing agents, including b 2 -adrenergic receptor (b 2 AR) agonists, which are mainstay of asthma therapy, and prostaglandin E2 (PGE2), inhibit the migration of HASM cells, although the mechanism for this migration remains unknown. Vasodilator-stimulated phosphoprotein (VASP), an anticapping protein, modulates the formation of actin stress fibers during cell motility, and is negatively regulated by protein kinase A (PKA)-specific inhibitory phosphorylation at serine 157 (Ser157). Here, we show that treatment with b 2 AR agonists and PGE2 induces the PKA-dependent phosphorylation of VASP and inhibits the migration of HASM cells. The stable expression of PKA inhibitory peptide and the small interfering (si) RNA-induced depletion of VASP abolish the inhibitory effects of albuterol and PGE2 on the migration of HASM cells. Importantly, prolonged treatment with albuterol prevents the agonist-induced phosphorylation of VASP at Ser157, and reverses the inhibitory effects of albuterol and formoterol, but not PGE2, on the basal and PDGF-induced migration of HASM cells. Collectively, our data demonstrate that b 2 AR agonists selectively inhibit the migration of HASM cells via a b 2 AR/PKA/ VASP signaling pathway, and that prolonged treatment with albuterol abolishes the inhibitory effect of b-agonists on the phosphorylation of VASP and migration of HASM cells because of b 2 AR desensitization.Keywords: airway hyperresponsiveness; b 2 -adrenergic receptor desensitization; protein kinase A; albuterol; formoterol Human airway smooth muscle (HASM) hyperplasia and remodeling are characteristic features of airways that contribute to their irreversible obstruction in patients with severe asthma. Accumulating evidence suggests that cell migration contributes to airway smooth muscle hyperplasia and remodeling (1, 2). Recently, the migration of airway smooth muscle (ASM) cells toward the epithelium and lumen of the airway was reported as a potential contributor to the increased smooth muscle mass in patients with asthma (3, 4). Further, cell-culture studies show that mitogens and inflammatory mediators involved in asthma pathogenesis and pharmacological agents in current used for the treatment of asthma modulate the migration of ASM cells (1,5,6). Taken together, these studies suggest that the migration of ASM cells contributes to ASM cell hyperplasia under asthmarelated conditions (1). Although the role of HASM hyperplasia in asthma is well established, the molecular mechanisms regulating the migration of HASM cells under asthma-related conditions are poorly understood (1).Evidence demonstrates that cyclic adenosine monophosphate (cAMP)-inducing agents, including the long-acting b 2 -adrenergic receptor (b 2 AR) agonist formoterol, inhibit the agonist-dependent migration of ASM cells (5, 7). We p...

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“…5). Certainly, therapeutic agents such as corticosteroids and even ␤ 2 -agonists can reduce proliferation (19,86). Furthermore, peroxisome proliferatoractivated receptor (PPAR)-␥ ligands can blunt ASM proliferation, migration, and ECM formation (63,72,73,250,293), and this mechanism may be of interest, given its emerging role in lung development and injury (180,220,247,260).…”