COPD is characterized by chronic bronchitis, emphysema, and pulmonary vascular remodelling. Alterations in the pulmonary vasculature, such as vessel wall thickening and increased oxidative/nitrosative stress, precede and may contribute to the development of emphysema. Key oxidative and nitrosative stress sources in COPD are NADPH oxidase organizer 1 (NOXO1) and inducible nitric oxide synthase (iNOS), respectively. However, the roles of oxidative and nitrosative stress in endothelial and smooth muscle cells during disease development remain unclear.

To address this, we utilized mice with inducible deletion of Noxo1 or iNOS in Tie2⁺ (endothelial) or Acta2⁺ (smooth muscle) cells, respectively, and exposed them to chronic cigarette smoke (CS) to model emphysema and COPD-associated vascular remodelling.

Our results show that deletion of Noxo1 or iNOS in Tie2⁺ cells protects against CS-induced vascular remodelling but not emphysema. Cytokine analysis revealed a distinct inflammatory signature associated with vascular remodelling that promotes vascular smooth muscle cell proliferation. Mice with Noxo1/iNOS deletion in Acta2⁺ cells were protected from CS-induced emphysema but developed vascular alterations. Further ex vivo analyses indicate that protection from emphysema in these animals is likely due to enhanced endogenous repair mechanisms in the alveolar regions adjacent to the vessels.

These findings suggest that oxidative/nitrosative stress in the different pulmonary vascular cells contributes to distinct COPD phenotypes. Further investigation is needed to elucidate the cellular mechanisms underlying alveolar repair following stress reduction in Acta2⁺ cells.