Extracellular matrix modulates beta2-adrenergic receptor signaling in human airway smooth muscle cells

Abstract

The airways of patients with chronic asthma commonly develop an element of fixed airway obstruction, which fails to reverse with inhaled beta2-adrenoceptor agonists. Airway remodeling refers to the structural changes of the bronchi in longstanding asthma and is characterized by increased deposition and altered ratios of extracellular matrix (ECM) proteins. We therefore assessed whether ECM proteins alter beta2-adrenoceptor signaling in human airway smooth muscle cells. We report that a fibronectin environment increases responses to beta2-adrenoceptor stimulation, whereas exposure to collagen V or laminin decreases accumulation of the second messenger cyclic AMP when compared with collagens I or IV. These differences are likely to be physiologically significant as they translate into altered phosphorylation of the downstream target VASP. The altered cAMP levels are due to differences in adenylyl cyclase activity, although expression of the relevant isoforms of enzyme appears unaltered. However, inhibition of Galphai abrogates the differences in beta2-adrenoceptor-mediated cAMP accumulation in cells exposed to different matrix factors. The difference in Galphai signaling is not due to altered Galphai expression. We conclude therefore that ECM modulates Galphai activity in human airway smooth muscle cells, and propose that these changes could contribute to the fixed airway obstruction seen in patients with chronic asthma.