Mitochondrial and Metabolic Drivers of Pulmonary Vascular Endothelial Dysfunction in Pulmonary Hypertension

Pulmonary hypertension (PH) is a deadly and increasingly prevalent vascular disease characterized by excessive pulmonary vascular remodeling and right ventricular dysfunction which leads to right heart failure, multiorgan dysfunction, and premature death. The cause of the vascular remodeling in PH remains elusive, and thus current treatments are marginally effective and prognosis of PH remains poor. Increasing evidence indicates the pathogenic importance of endothelial dysfunction in PH. However, the underlying mechanisms of such dysfunction are not well described. Endothelial apoptosis and hyperproliferation have been identified in patients with PH. Both are linked with the increased oxidative stress and inflammatory responses, and are influenced by various genetic and exogenous stresses. Importantly, contrary to historic dogma that suggested a negligible role for mitochondria and energy balance in endothelial pathology, recent findings have implicated the role of endothelial metabolism directly in PH. This chapter addresses the emerging role of mitochondria in pulmonary vascular endothelial dysfunction in PH. A more sophisticated understanding of the biochemical, metabolic, molecular, and physiologic underpinnings of this emerging paradigm should enable the development of a new generation of targeted therapies that will stunt or reverse pulmonary vascular remodeling.