Store-operated Ca²⁺ entry contributes to the ASM phenotype transition in asthma

Phenotype modulation of airway smooth muscle cells (ASMC), characterized by a shift toward a more proliferative and synthetic phenotype from contractile cells, plays a crucial role in airway remodeling in asthma. STIM1 and Orai1, key components of store-operated Ca²⁺ entry (SOCE), have been demonstrated to enhance ASMC proliferation and migration. This study investigated the impact of STIM1/Orai1-mediated SOCE on ASMC phenotype transition and extracellular matrix (ECM) deposition in asthma.

The ASMCs were treated with PDGF-BB and SOCE inhibitors. Immunocytochemistry staining, enzyme-linked immunosorbent assay, and western blot assay were employed to detect the ASMC's proliferation as well as the expressions of contractile proteins, inflammatory cytokines and ECM. Moreover, the effect of SOCE repression in ECM deposition were evaluated in an asthmatic mouse model.

ASMCs from airways of mice were treated with PDGF-BB to induce the 'proliferative/synthetic' phenotype. We observed elevated expressions of STIM1 and Orai1 in phenotype-switched ASMCs, along with enhanced SOCE. SKF-96365 and RO2959, which target of STIM1/Orai1, could significantly inhibit SOCE activation in ASMCs. Moreover, these SOCE inhibitors mitigated the elevated proliferation rate, decreased the secretion of inflammatory cytokines and restored the reduced levels of contractile proteins in phenotype-switched ASMCs induced by PDGF-BB. Furthermore, we observed that PDGF-BB-induced 'proliferative/synthetic' ASMCs exhibited increased production of ECM components, including collagen I and fibronectin, as well as metalloproteinases (MMPs) such as MMP2 and MMP9, all of which were effectively inhibited by SKF-96365 and RO2959. In vivo experiments also demonstrated that SOCE inhibitors decreased ECM deposition and MMPs production in the asthmatic mouse model.

These findings underscored the significant role of STIM1/Orai1-mediated SOCE in ASMC phenotype modulation and its impact on the excessive ECM deposition driven by ASMCs. Thus, our findings suggest that STIM1/Orai1-mediated SOCE may contribute to airway remodeling in asthma.