Scripta Medica (Jan 2012)
Transforming growth factor-beta superfamily members in the pathogenesis of pulmonary arterial hypertension
Abstract
Pulmonary arterial hypertension (PAH) is a devastating and rapidly progressing disease that induces substantial pulmonary vascular remodeling. The pathologic changes especially in pulmonary microvasculature result in progressive increases in the mean pulmonary artery pressure and pulmonary vascular resistance, which, if untreated leads to right-ventricular failure and death. Although it is clear that PAH has a multifactorial pathobiology, recent discoveries pointed out crucial role of Transforming Growth Factor (TGF)-beta family members in the pathophysiology of PAH. The TGF-beta superfamily is composed of multifunctional mediators, including the TGF-beta isoforms and the Bone Morphogenetic Proteins (BMPs). Germline mutations in the gene coding for BMP receptor 2 (BMPR2) have been identified in 60% of familial and 10-30% of idiopathic PAH. Mutations in the TGF-beta receptors, ALK-1 and endoglin, have been found in PAH patients with a personal or family history of hereditary hemorrhagic telangiectasia. Non-canonical TGF-beta pathways as well as TGF-beta receptor ligands (i.e. BMP9) are also involved in PAH development. Our improved understanding of TGF-beta pathway regulation will have important implications for the development of novel therapeutic strategies for this complex and serious disease. Animal models will undoubtedly have an important role in this process; however human studies will give the fi nal answer about the efficacy and safety of the novel treatments for PAH. This review provides an overview of the TGF-beta and BMPs potential role in PAH.
