Pathobiology of pulmonary artery hypertension

Primary or secondary pulmonary hypertension (PH) is an unexplained condition whose severe forms in adults or neonates are fatal and for which no satisfactory treatment is available. Considerable progress has been achieved over the last few years in our understanding of this disease, both through genetic studies that have identified mutations in the gene for BMP-RII (bone morphogenetic protein receptor II) in patients with familial primary PH (PPH) and through pathophysiological investigations that have elucidated the molecular mechanisms involved in hypertrophic arterial wall remodelling, most notably the role for the serotonin transporter (5-HTT) in hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs). Identification of the BMP (bone morphogenetic protein) pathway as relevant to the aetiology of PPH now raises many questions about the link between the BMP-RII mutant genotype and the PPH phenotype. That PPH does not develop in all subjects with BMP-RII mutations suggests a crucial role for environmental or associated genetic factors. Simultaneously, mechanistic studies investigating the biological processes that underlie the complex vascular changes associated with PPH have identified major molecular pathways involved in constriction and proliferation of pulmonary vascular smooth muscle cells, dysfunction of endothelial cells, and remodelling of extracellular matrix. Such mechanisms may be involved either in initiating or in perpetuating the disease. The finding that genetic polymorphism of some of the candidate genes related to these processes is closely associated with PPH suggests a causal relationship between the expression, or function, of these genes and the PPH phenotype. The association between PPH and the L allelic variant of the serotonin transporter (5-HTT) gene indicates that 5-HTT which controls smooth muscle hyperplasia, probably contributes to susceptibility to PPH or is an important modifier of the PPH phenotype. Recognition of these molecular pathways should provide insight into the pathogenesis not only of primary PH, but also of secondary forms of PH. This should lead soon to the development of new and more selective therapeutic approaches to pulmonary hypertension.