Therapeutics targeting of dysregulated redox equilibrium and endothelial dysfunction.

All forms of WHO Group 1 PAH share a progressive and complex vasculopathy. At the center of this derangement lies the pulmonary vascular endothelium, which plays a crucial role in maintaining a delicate and precise balance of opposing vasoconstricting and vasodilating forces. In PAH, endothelial cell damage and dysfunction alter vascular homeostasis in favor of vasoconstriction. There is evidence of increased expression and activity in the vasoconstrictor and mitogen endothelin-1 signaling system and a decreased production of the potent vasodilator prostacyclin. These pathways have been a major focus of FDA approved PAH-specific therapies. Beyond these pathways, there is the dysfunction within the endothelial nitric oxide (NO) synthase signaling pathway and dysregulation of reactive oxygen and nitrogen species (ROS) that contribute to the pathogenesis of PAH. The dysregulation of vasodilator systems in PAH in large part involves the NO pathway, with almost every step subject to impairments. This includes a reduction in endothelial NO synthase function (eNOS), the enzymatic "uncoupling" of eNOS, increased scavenging of NO by superoxide and cell-free hemoglobin, the elaboration of endogenous competitive inhibitors of eNOS (ADMA), and the oxidation of the NO target, soluble guanylyl cyclase. The dysregulation of NO signaling pathways occurs in the setting of parallel upregulation of vascular oxidases that generate ROS. Enzymatic sources of ROS in PH that have been identified include the NAPDPH oxidases 1, 2, and 4, xanthine oxidase, uncoupled eNOS, and complex III of the mitochondrial electron transport chain. Superoxide produced from these sources reacts with NO to form the reactive nitrogen species peroxynitrate, further diverting bioavailable NO to more injuries species. In PAH, this upstream dysregulation of ROS/NO redox homeostasis severely impairs vascular tone and contributes to the pathological activation of mitogenic pathways, leading to cellular proliferation and obliteration of the pulmonary vasculature. Therapeutic strategies are being evaluated that target the associated dysregulated redox equilibrium and endothelial dysfunction in PAH. Therapeutic interventions reviewed in this chapter include NO donor or NO generating drugs, therapies that recouple eNOS or directly increase cGMP levels via inhibition of phosphodiesterase 5 or stimulation of soluble guanylyl cyclase, and therapies that inhibit vascular oxidases or scavenge ROS.