Endothelial Cell Global Positioning System for Pulmonary Arterial Hypertension
Homing in on Vascular Repair
Pulmonary arterial hypertension (PAH), defined as a mean pulmonary artery pressure exceeding 25 mm Hg in the presence of a normal capillary wedge pressure,1 is an infrequent (reported incidence, 1–2 per million), chronic, and eventually fatal disorder characterized by obliterative microvascular changes, endothelial cell (EC) dysfunction, and vascular smooth muscle cell overgrowth. The cause of PAH varies (idiopathic, familial, or secondary to autoimmune phenomena and infections such as human immunodeficiency virus), but overall outcome (median survival, 2.8 years) is universally poor.2
See accompanying article on page 1539
Current treatment algorithms involve general supportive measures and pharmacotherapy (calcium channel blockers, anticoagulants, diuretics), as well as targeting major pathways that regulate pulmonary vascular tone: endothelin, nitric oxide, and cAMP.3 Therapeutic agents, such as endothelin receptor antagonists (bosentan), cGMP-specific phosphodiesterase type 5 inhibitors (sildenafil), soluble guanylate cyclase activators (riociguat), and prostacyclin analogs that increase cAMP production (epoprotenol), provide symptomatic benefit and increased functional capacity.4 However, they fail to substantially improve life expectancy or reverse the underlying disease process. Potentially curative therapies, other than lung transplantation (which itself has significant attendant morbidity secondary to chronic immunosuppression), that directly modulate the underlying pathogenesis of PAH remain elusive.
Although there remains much to understand regarding the cause of PAH, novel therapeutic interventions have been developed to enable mitigation of disease in preclinical (animal) models by targeting known activated pathways in PAH. Preventing disease progression by …