Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease affecting the pulmonary arteries. The hallmark of IPAH is excessive vascular remodelling of the pulmonary arteries, a well coordinated process, where all cell types of the vessel wall participate. The discovery that mutations in the gene coding for the bone morphogenetic protein receptor type 2 (bmpr2) as well as for the activin receptor-like kinase 1 (alk1), both members of the transforming growth factor (TGF)-beta receptor superfamily, infamilial (IPAH) and secondary (SPAH) pulmonary arterial hypertension, respectively, suggest that the TGF-beta signalling cascade is important for the maintenance of the pulmonary vascular homeostasis and disease development. Hence, the aim of this study was to elucidate the role of the TGF-beta signalling cascade in the development of IPAH focusing on two aspects. First, the proliferation, migration and adhesion of pulmonary arterial smooth muscle cells and second the extracellular matrix deposition.Differential expression analysis between donor and IPAH lung homogenates revealed that the plasminogen activator inhibitor type I (PAI-1), a TGF-beta1 target gene, is significantly downregulated in IPAH lung homogenates, both on the mRNA and protein levels. Further in vitro experiments revealed that PAI-1 regulates PASMC proliferation, migration and adhesion and, therefore, could be a potential regulator of vascular remodelling in IPAH. Furthermore, the deposition of hyaluronic acid (HA), which is an important component of the lung extracellular matrix, is greatly increased in IPAH lungs compared to donors, due to increased levels of hyaluronan synthase 1 (HAS1), which is responsible for HA synthesis, and decreased levels of hyaluronoglucosamininidase 1(HYAL1), which degrades HA. In vitro experiments in PASMC revealed that TGF-beta1 controls the levels of HA by regulating HAS1 expression levels.In summary, TGF-beta1 is a potent regulator of vascular remodelling contributing to IPAH, by controlling the levels of PAI-1 and HA.
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