Metabolism and Redox in Pulmonary Vascular Physiology and Pathophysiology.

Significance: This review considers how some systems controlling pulmonary vascular function are potentially regulated by redox processes to examine how and why conditions such as prolonged hypoxia, pathological mediators, and other factors promoting vascular remodeling contribute to the development of pulmonary hypertension (PH). Recent Advances and Critical Issues: Aspects of vascular remodeling induction mechanisms described are associated with shifts in glucose metabolism through the pentose phosphate pathway and increased cytosolic NADPH generation by glucose-6-phosphate dehydrogenase, increased glycolysis generation of cytosolic NADH and lactate, mitochondrial dysfunction associated with superoxide dismutase-2 depletion, changes in reactive oxygen species and iron metabolism, and redox signaling. Future Directions: The regulation and impact of hypoxia-inducible factor and the function of cGMP-dependent and redox regulation of protein kinase G are considered for their potential roles as key sensors and coordinators of redox and metabolic processes controlling the progression of vascular pathophysiology in PH, and how modulating aspects of metabolic and redox regulatory systems potentially function in beneficial therapeutic approaches.