Chronic obstructive pulmonary disease (COPD) is an incurable disease. Besides chronic bronchitis and pulmonary emphysema, pulmonary vascular remodelling is often observed in COPD patients. The primary cause is prolonged exposure to harmful substances, such as cigarette smoke (CS) and pollutants. Upon CS exposure, a source of nitrosative/oxidative stress - inducible nitric oxide synthase (iNOS) was increased in pulmonary vessels. Treatment of iNOS inhibitor, L-NIL, reverses CS-induced emphysema in a pre-clinical mouse model. However, the alveolar repair mechanisms driven by pulmonary vasculature remain poorly investigated.

To explore the therapeutic potential of iNOS-ablation in pulmonary artery smooth muscle cells (PASMCs), we employed a transgenic mouse model with a cell-specific Cre/loxP system (Acta2-CreERT2/iNosflox/flox). Mice were exposed to CS for 8 months to induce emphysema, followed by 3 months of CS cessation after tamoxifen-activated iNOS deletion. Lung function measurements were performed, and lung samples were collected for precision-cut lung slices (PCLS) generation, single-cell transcriptome profiling, and histological/stereological analyses.

Strikingly, deletion of iNOS in Acta2⁺ cells reversed established CS-induced emphysema evident by reduced lung compliance, decreased mean linear intercept, and increased number of alveoli. Reducing the stress increased the number of proliferative cells in the proximity of vascular compartment in PCLS. Single-cell transcriptome profiling further revealed a downregulation of contractile markers in PASMCs from iNOS-deleted mice. Future studies will decipher molecular landscape underlying PASMC-mediated reparative process.