PECs from patients with iPAH exhibited Smad1/5/8 phosphorylation in response to increasing doses of TGF-b; medium from PECs treated with TGF-b markedly increased SB 218078 PA-SMC growth, and this effect seemed related to induction by TGF-b of ET-1, PDGFb, and FGF2 expression in PECs and disappeared in the presence of anti-ENG antibody; and ENG-deficient mice were partly protected Ifenprodil hemitartrate against chronic hypoxia-induced PAH to wildtype mice, a finding that seemed related to decreased expression of PDGFa, PDGFb, and FGF2, three factors playing a key role in vascular remodeling and in the development of human and experimental PAH. ALK1 and ENG mutations have been associated with HHT and, to a lesser extent, heritable PAH, two familial vascular dysplasias with apparently opposite phenotypes. Thus, HHT is characterized by dilated vessels, telangiectasia, and arteriovenous malformations in the lung, liver, and brain. In the lungs, the arteriovenous malformations can result in right-to-left shunts, leading to severe cyanosis and dyspnea, and potentially to the development of pulmonary vascular remodeling with PAH. Various physiological factors, such as blood flow or pressure, have been shown to trigger the vessel remodeling process, which involves PA-SMC proliferation and extracellular matrix protein synthesis and accumulation. Taken in concert, these data highlight the importance of the TGF-b/ ALK1/ENG signaling pathway in maintaining vascular integrity. Increased expression of TGF-b and its receptors ALK1 and ENG led to an increase in TGF-b/ALK1/ENG signaling activity in lung tissue and PECs from iPAH patients. Several studies have assessed the contribution of TGF-b to PAH, which remains debated. A recent study found decreased pulmonary TGF-b mRNA expression in PAH patients, contrasting with increases in TGF-b1 or TGF-b isoforms 2 and 3 in previous studies. These discrepancies may be ascribable to differences in measurement techniques: the previous studies relied on mRNA analysis or TGF-b protein measurement in pulmonary arteries, whereas we measured both lung and serum TGF-b protein contents. Upregulation of TGF-b has also been reported in several animal models of PAH, and decreased TGF-b signaling related to dominant negative TGF-b type II receptor overexpression or anti-TGF-b antibody protects against PAH. Over the last 10 years, the importance of ALK1 and ENG in the pathogenesis of PAH has been established, notably by the identification of gene mutations.