Physiopathologie du remaniement vasculaire pulmonaire au cours de l’hypertension artérielle pulmonaire

Abstract

Recent years have witnessed important advances in our understanding of the pathophysiology of primary pulmonary hypertension (PPH). Both genetic and mechanistic studies have succeeded in identifying new molecular pathways relevant to the process of pulmonary vascular remodelling which underlies PPH. Mutations in the type II bone morphogenetic protein receptor (BMPRII) are now considered to be the genetic basis for familial PPH and about 30% of cases of sporadic PPH. Identification of the BMP pathway as relevant to the aetiology of PPH now raises many questions about the link between the BMPRII mutant genotype and the PPH phenotype. That PPH does not develop in all subjects with BMPRII 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 (SMCs), 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.