Pulmonary arterial hypertension (PAH) is a devastating disease, with an annual incidence of 1-2 patients per 106 population. Clinically, it is characterized by a sustained elevation of the mean pulmonary arterial pressure of more than 25 mmHg at rest and more than 30 mmHg during exercise, while in the healthy human it is ranging between 12 and 16 mmHg. Although the disease may occur at any age, PAH is usually diagnosed in the 4th decade of life, with a female-to-male ratio of 1.7:1, but in children the ratio between genders is almost equal. PAH occurs as an idiopathic disease (called idiopathic PAH, iPAH) and as a consequence of other illnesses, including connective tissue diseases, portal hypertension, diet and stimulant drug use, human immunodeficiency virus (HIV) infection, and congenital heart disease. Pulmonary arterial hypertension also occurs as a familial form, which is almost always due to mutations in genes of the transforming growth factor (TGF)-ß superfamily of receptors. The most common mutation leading to PAH is in the gene encoding bone morphogenetic protein receptor type II (BMPR-2), which was originally discovered to be involved in bone healing. Recent studies on the TGF-ß signalling pathway have reported mutations in the activin receptor-like kinase 1 (ALK1) gene, which belongs to the same family of receptors, with a mechanism similar to that of BMPR-2. The reported mutations have been observed in patients with hereditary hemorrhagic telangiectasia (HHT) in association with PAH. Evidence is emerging that imbalanced activation of other TGF-ß receptors may increase the likelihood of the development of PAH. Many signaling pathways have been found to participate in PAH, including K channels, serotonin, angiopoietin, and cyclooxygenases. The interaction of these signaling systems with the TGF-ß system, is currently a focus of research in PAH. Approaches to altering the imbalance in activation of BMPR-2, ALK1 and other TGF-ß; receptors may yield future therapies for PAH.Due to the complexity of the TGF-ß system and its documented causal role in PAH, we sought to analyze the expression and localization patterns of TGF-ß/BMP receptors and Smads in chronic hypoxia-induced pulmonary hypertension over time, as well as in the lungs of patients with iPAH. The expression of the TGF-ß/BMP receptors in the mouse model of hypoxia-induced pulmonary hypertension revealed decreased expression of ALK1, ALK3 and TGFß-R2 mRNA level in lungs of animals exposed to hypoxia for three weeks, compared with normoxia-treated controls, and no change in BMPR-2 mRNA levels. Among the pathway mediators, only Smad7 and Smad8 were downregulated at mRNA level after three weeks of hypoxia. The protein expression of ALK1, TGFß-R2, Smad1 and Smad4 was significantly downregulated after three weeks at hypoxia exposure. The localization of these molecules was then assessed, and staining for these molecules was observed in the bronchial epithelial cells and pulmonary arterial smooth muscle cells (PASMC), and in the heart muscle cells surrounding intrapulmonary veins. These changes were limited to the animal model of hypoxia-induced pulmonary hypertension, as not all changes in expression were observed in lungs from iPAH patients, with the exception of ALK1, which was downregulated in iPAH patients. Activin receptor like kinase 1 (ALK1), is well described to be expressed and active in endothelial cells (EC), however the expression of this receptor in smooth muscle cells represents a novel aspect of this work, and an attractive novel pathophysiological area and research subject on smooth muscle cell proliferation in PAH.
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