In conclusion, two main findings were demonstrated in this study (1) distal arteriolar remodeling and changes in proximal pulmonary artery blood rheology, structure and function of the right heart might occur before a definite PH in COPD patients [65]; (2) TGFβ-triggered NADPH oxidase-ROS signaling cascade, particularly the NOX4/ROS signaling was involved in the development of pulmonary arteriole remodeling and PAH in COPD (Fig. 11). Here, FMO5 is linked to pulmonary arterial hypertension.