Abstract-Mutations in the bone morphogenetic protein type II receptor gene (BMPR2) are the major genetic cause of familial pulmonary arterial hypertension (FPAH). Although smooth muscle cell proliferation contributes to the vascular remodeling observed in PAH, the role of BMPs in this process and the impact of BMPR2 mutation remains unclear. Studies involving normal human pulmonary artery smooth muscle cells (PASMCs) suggest site-specific responses to BMPs. Thus, BMP-4 inhibited proliferation of PASMCs isolated from proximal pulmonary arteries, but stimulated proliferation of PASMCs from peripheral arteries, and conferred protection from apoptosis. These differences were not caused by differential activation of BMP signaling pathways because exogenous BMP-4 led to phosphorylation of Smad1, p38 MAPK , and ERK1/2 in both cell types. However, the proproliferative effect of BMP-4 on peripheral PASMCs was found to be p38 MAPK /ERK-dependent. Conversely, overexpression of dominant-negative Smad1 converted the response to BMP-4 in proximal PASMCs from inhibitory to proliferative. Furthermore, we confirmed that proximal PASMCs harboring kinase domain mutations in BMPR2 are deficient in Smad signaling and are unresponsive to the growth suppressive effect of BMP-4. Moreover, we show that the pulmonary vasculature of patients with familial and idiopathic PAH are deficient in the activated form of Smad1. We conclude that defective Smad signaling and unopposed p38 MAPK /ERK signaling, as a consequence of mutation in BMPR2, underlie the abnormal vascular cell proliferation observed in familial PAH. Key Words: vascular remodeling Ⅲ pulmonary hypertension Ⅲ transforming growth factor-␤ Ⅲ smooth muscle cells Ⅲ cell signaling P rimary, or idiopathic, pulmonary arterial hypertension (IPAH) is a rare disorder that is progressive and often fatal, leading to death within a median of 3 years from right ventricular failure without treatment. 1 The disease is characterized by vascular cell proliferation and obliteration of small pulmonary arteries by smooth muscle cells and myofibroblasts. 2 In addition, plexiform lesions comprising endothelial cells and myofibroblasts are found in Ϸ50% of cases. 3 Genetic studies have revealed heterozygous mutations in the BMPR2 gene encoding the type II bone morphogenetic protein receptor (BMPR-II), a member of the TGF-␤ superfamily of receptors, 4,5 underlying the familial form of the disease (FPAH). Subsequently, BMPR2 mutations were found in Ϸ25% of apparently sporadic cases of IPAH, many of which are examples of familial transmission with low disease gene penetrance. 6,7 Although these genetic studies point toward a critical role for the TGF-␤ superfamily in the regulation of pulmonary vascular cell growth and differentiation, the precise molecular mechanisms leading to disease pathogenesis remain to be elucidated.Signaling by BMP receptors involves heterodimerization of 2 transmembrane serine/threonine kinases: the constitutively active type II receptor, BMPR-II, and a corresponding type I re...

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Abstract-Heterozygous germline mutations in the gene encoding the bone morphogenetic protein type II (BMPR-II) receptor underlie the majority (Ͼ70%) of cases of familial pulmonary arterial hypertension (FPAH), and dysfunction of BMP signaling has been implicated in other forms of PAH. The reduced disease gene penetrance in FPAH indicates that other genetic and/or environmental factors may also be required for the clinical manifestation of disease. Of these, the serotonin pathway has been implicated as a major factor in PAH pathogenesis. We investigated the pulmonary circulation of mice deficient in BMPR-II (BMPR2 ϩ/Ϫ mice) and show that pulmonary hemodynamics and vascular morphometry of BMPR2 ϩ/Ϫ mice were similar to wild-type littermate controls under normoxic or chronic hypoxic (2-to 3-week) conditions. However, chronic infusion of serotonin caused increased pulmonary artery systolic pressure, right ventricular hypertrophy, and pulmonary artery remodeling in BMPR2 ϩ/Ϫ mice compared with wild-type littermates, an effect that was exaggerated under hypoxic conditions. In addition, pulmonary, but not systemic, resistance arteries from BMPR2 ϩ/Ϫ mice exhibited increased contractile responses to serotonin mediated by both 5-HT 2 and 5-HT 1 receptors. Furthermore, pulmonary artery smooth muscle cells from BMPR2 ϩ/Ϫ mice exhibited a heightened DNA synthesis and activation of extracellular signal-regulated kinase 1/2 in response to serotonin compared with wild-type cells. In vitro and in vivo experiments suggested that serotonin inhibits BMP signaling via Smad proteins and the expression of BMP responsive genes. These findings provide the first evidence for an interaction between BMPR-II-mediated signaling and the serotonin pathway, perturbation of which may be critical to the pathogenesis of PAH. Key Words: pulmonary arterial hypertension Ⅲ bone morphogenetic protein Ⅲ serotonin I diopathic pulmonary arterial hypertension (IPAH) is characterized by narrowing and obliteration of the small arteries of the lung leading to increased pulmonary vascular resistance. 1 Elevation of pulmonary arterial pressure leads to right ventricular failure. Patients present with dyspnea after exertion, and many died of right heart failure within 3 years of diagnosis, before modern therapies. 2 Treatment with prostanoids or endothelin receptor antagonists improves symptoms and survival, although, for many, the long-term outlook remains poor.Heterozygous germline mutations in the gene encoding the bone morphogenetic protein type II receptor (BMPR-II) occur in up to 70% of cases of familial PAH (FPAH). 3,4 Similar mutations were found in up to 26% of cases of idiopathic PAH. 5 However, the low disease gene penetrance suggests that other genetic or environmental factors are necessary to manifest clinical disease.A series of studies have implicated serotonin (or 5-HT) as a key mediator of PAH. 6 -8 For example, treatment of rats with serotonin potentiates the effects of hypoxia on pulmonary arterial pressure, right ventricular hypertrophy an...