Abstract Body (Do not enter title and authors here): Background: The severity of chronic obstructive pulmonary disease (COPD) is significantly worsened by the development of pulmonary hypertension (PH), a complication associated with increased mortality and with an unclear pathogenesis. Addressing this knowledge gap requires elucidating the underlying mechanisms through effective animal models. Hypothesis: We hypothesized that subacute CS exposure during hypoxic conditions is sufficient to cause pulmonary artery remodeling (PA remodeling) and to model COPD-PH. In addition to pathophysiological endpoints of PA remodeling, we also inquired whether the disintegrin ADAM metallopeptidase domain-9 (ADAM9) is increased in the lungs of mice with PA remodeling, as reported in human COPD-PH lungs. Methods: We simultaneously exposed mice to cigarette smoke (CS; 5hrs/weekdays) and normobaric hypoxia (Hx; 12% FiO2) for six weeks (n = 4 per group; 2 females and 2 males). Right ventricle hypertrophy was evaluated by Fulton index. Hemodynamic and pulmonary function were assessed using right heart catheterization and FlexiVent measurements, respectively. PA remodeling was evaluated by α-smooth muscle actin (α-SMA; %) immunofluorescence. ADAM9 levels from snap-frozen lung tissues were quantified by densitometry analysis of Western blots. Data was analyzed using Student’s t-test or one-way ANOVA with a Tukey HSD post hoc analysis, as well as Pearson’s correlation test. Results: Mice exposed to CS-Hx exhibited increased right ventricular mass compared to normoxic air control (AC) and CS-only groups by 17% and 30% (p=0.01 and 0.0007, respectively) and higher right ventricular systolic pressure (30 mmHg and 27 mmHg in AC, p=0.37). The lung static compliance and inspiratory capacity were significantly increased in CS-Hx mice vs. the AC group (p=0.03 and 0.02, respectively). Immunofluorescence analysis revealed a higher abundance of α-SMA in the pulmonary walls of CS-Hx mice compared to the AC group (p=0.06). ADAM9 abundance was significantly higher in the CS-Hx group compared to the AC and the CS only groups by 3.9- and 1.4 -fold (p=0.02 and 0.03), respectively. ADAM9 levels correlated positively with Fulton index (r=0.72, p=0.005) and inspiratory capacity (r=0.56, p=0.04). Conclusion: Exposure to subacute duration of CS-Hx induces a COPD-PH phenotype in mice, making this an appropriate model for studying COPD-PH. Similar to human COPD-PH, ADAM9 was increased, suggesting it plays a significant role in the pathogenesis of COPD-PH.