Pathobiology of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a syndrome of dyspnea, fatigue, chest pain and syncope defined by an increase in pulmonary vascular resistance (PVR) of unknown cause. The pathobiology of PAH remains incompletely understood. The gene of the idiopathic form of PAH (IPAH) has been located on chromosome 2, and shown to present mutations of a sequence that encodes for a transforming growth factor receptor, bone morphogenenetic protein receptor 2 (BMPR2). Severe pulmonary hypertension is associated with an increased expression of the angiogenic factor, angiopoietin-1, which shuts off the expression of BMPR1A, a transmembrane protein necessary for BMPR2 signalling, and thereby causes pulmonary artery smooth muscle cell proliferation. Additional biological abnormalities have been identified at all pulmonary arterial wall compartments of PAH patients. The endothelium produces an excess of endo-thelin, a potent vasoconstrictor and mitogenic mediator, while synthesis and release of antagonistic prostacyclin and nitric oxide is decreased. Pulmonary vascular smooth muscle cells present with an increased expression of a serotonin transporter, allowing for vasoconstrictive and mitogenic effects of increased circulating serotonin, and also show an increased expression of voltage-dependent potassium channels, which also promotes vasoreactivity and proliferation. The adventitial matrix bound metalloprotases appear to be activated in relation to increased serine elastase, leading to increased production of tenascin, a potent mitogen. While none of these abnormalities isolately explains PAH, their identification has already led to efficient therapeutic interventions, including the administration of prostacyclin derivatives and anti-endothelin compounds.