Kisspeptin/KISS1R Signaling Modulates Human Airway Smooth Muscle Cell Migration

Airway remodeling is a cardinal feature of asthma, associated with increased airway smoothmuscle (ASM) cellmass andupregulationof extracellularmatrix deposition. Exaggerated ASMcellmigration contributes to excessive ASMmass. Previously, we demonstrated the alleviating role of Kp (kisspeptin) receptor (KISS1R) activation by Kp-10 inmitogen (PDGF [platelet-derived growth factor])-induced human ASMcell proliferation in vitro and airway remodeling in vivo in amousemodel of asthma. Here, we examined themechanisms by which KISS1R activation regulatesmitogen-induced ASM cell migration. KISS1R activation using Kp-10 significantly inhibited PDGF-induced ASMcellmigration, further confirmed using KISS1R shRNA. Furthermore, KISS1R activationmodulated F/G actin dynamics and the expression of promigration proteins like CDC42 (cell division control protein 42) and cofilin. Mechanistically, we observed reduced ASM RhoA-GTPAse with KISS1R activation. The antimigratory effect of KISS1R was abolished by PKA (protein kinase A)-inhibitory peptide. Conversely, KISS1R activation significantly increased cAMP and phosphorylation of CREB (cAMP-response element binding protein) in PDGF-exposed ASMcells. Overall, these results highlight the alleviating properties of Kp-10 in the context of airway remodeling.