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Serotonin Increases Susceptibility to Pulmonary Hypertension in BMPR2-Deficient Mice

Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Cambridge, United Kingdom.
Circulation Research (Impact Factor: 11.09). 04/2006; 98(6):818-27. DOI: 10.1161/01.RES.0000215809.47923.fd
Source: PubMed

ABSTRACT Heterozygous germline mutations in the gene encoding the bone morphogenetic protein type II (BMPR-II) receptor underlie the majority (>70%) 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(+/-) mice) and show that pulmonary hemodynamics and vascular morphometry of BMPR2(+/-) 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(+/-) mice compared with wild-type littermates, an effect that was exaggerated under hypoxic conditions. In addition, pulmonary, but not systemic, resistance arteries from BMPR2(+/-) mice exhibited increased contractile responses to serotonin mediated by both 5-HT2 and 5-HT1 receptors. Furthermore, pulmonary artery smooth muscle cells from BMPR2(+/-) 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.

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    • "To investigate the role of BMP signaling in the pancreas, we used a mouse line with a genetic deletion of BMPR2 in this study. BMPR2 deletion in homozygous mice (BMPR2−/−) results in embryonic lethality [16], heterozygous BMPR2+/− mice are phenotypically normal and can develop pulmonary hypertension upon inflammatory insults [25], [26]. Therefore, the heterozygous BMPR2+/− mice were used under CP induction in comparison with their littermate wild-type mice. "
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    ABSTRACT: Bone morphogenetic proteins (BMPs) have an anti-fibrogenic function in the kidney, lung, and liver. However, their role in chronic pancreatitis (CP) is unknown. The aim of this study was to define the anti-fibrogenic role of BMP signaling in the pancreas in vivo under CP induction. Mice with a deletion of BMP type II receptor (BMPR2(+/-)) were used in this study in comparison with wild-type mice. CP was induced by repetitive cerulein injection intraperitoneally for 4 weeks, and the severity of CP was evaluated. Pancreatic stellate cells (PSCs) were isolated from the mice and treated with BMP2 and TGF-β in vitro, and extracellular matrix protein (ECM) production was measured. Smad and mitogen-activated protein kinase (MAPK) signaling was also evaluated. BMPR2(+/-) mice revealed a greater pancreatic fibrosis, PSC activation and leukocyte infiltration after CP induction compared to wild-type mice (P<0.05). Under CP induction, phospho (p)Smad1/5/8 was elevated in wild-type mice and this effect was abolished in BMPR2(+/-) mice; pSmad2 and pp38(MAPK) were further enhanced in BMPR2(+/-) mice compared to wild-type mice (P<0.05). In vitro, BMP2 inhibited TGF-β-induced ECM protein fibronectin production in wild-type PSCs; this effect was abolished in BMPR2(+/-) PSCs (P<0.05). In BMPR2(+/-) PSCs, pSmad1/5/8 level was barely detectable upon BMP2 stimulation, while pSmad2 level was further enhanced by TGF-β stimulation, compared to wild-type PSCs (P<0.05). BMPR2/Smad1/5/8 signaling plays a protective role against cerulein-induced pancreatic fibrosis by inhibiting Smad2 and p38(MAPK) signaling pathways.
    PLoS ONE 02/2014; 9(2):e89114. DOI:10.1371/journal.pone.0089114 · 3.23 Impact Factor
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    • "Mice with Bmpr2 mutations have been used to study how human BMPR2 mutations might predispose carriers to PAH. Bmpr2+/- mice express about 50% of Bmpr2+ mRNA levels and manifest little [18] or no [23,24] pulmonary hypertension at baseline; however, pulmonary hypertension induced by an inflammatory stress [24] or an infusion of serotonin [23] is more marked in Bmpr2+/- than in WT mice. Mice carrying one copy of a mutant Bmpr2 allele lacking exon 2 (Bmpr2ΔE2) do not manifest pulmonary hypertension at baseline but develop more marked pulmonary hypertension after prolonged exposure to hypoxia [25]. "
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    ABSTRACT: The bone morphogenetic protein (BMP) type II receptor (BMPR2) has a long cytoplasmic tail domain whose function is incompletely elucidated. Mutations in the tail domain of BMPR2 are found in familial cases of pulmonary arterial hypertension. To investigate the role of the tail domain of BMPR2 in BMP signaling, we generated a mouse carrying a Bmpr2 allele encoding a non-sense mediated decay-resistant mutant receptor lacking the tail domain of Bmpr2. We found that homozygous mutant mice died during gastrulation, whereas heterozygous mice grew normally without developing pulmonary arterial hypertension. Using pulmonary artery smooth muscle cells (PaSMC) from heterozygous mice, we determined that the mutant receptor was expressed and retained its ability to transduce BMP signaling. Heterozygous PaSMCs exhibited a BMP7‑specific gain of function, which was transduced via the mutant receptor. Using siRNA knockdown and cells from conditional knockout mice to selectively deplete BMP receptors, we observed that the tail domain of Bmpr2 inhibits Alk2‑mediated BMP7 signaling. These findings suggest that the tail domain of Bmpr2 is essential for normal embryogenesis and inhibits Alk2‑mediated BMP7 signaling in PaSMCs.
    PLoS ONE 10/2013; 8(10):e76947. DOI:10.1371/journal.pone.0076947 · 3.23 Impact Factor
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    • "Genetic ablation of BMPR2 proves lethal due to lack of mesoderm [56], while BMPR2+/− mice do not spontaneously develop PAH. However, when BMPR2+/− mice are exposed to a secondary insult (e.g., serotonin), increased pulmonary artery pressures and pulmonary remodeling ensues [57]. This strengthens the idea that BMPR2 mutations predispose patients to develop PAH and that other factors are involved in developing the disease. "
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    ABSTRACT: Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH.
    Cellular and Molecular Life Sciences CMLS 06/2013; 70(23). DOI:10.1007/s00018-013-1382-5 · 5.86 Impact Factor
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