Circulation Research. 2006;98:818-827
Published online before print February 23, 2006, doi: 10.1161/01.RES.0000215809.47923.fd
Published online before print February 23, 2006, doi: 10.1161/01.RES.0000215809.47923.fd
© 2006 American Heart Association, Inc.
Integrative Physiology |
Serotonin Increases Susceptibility to Pulmonary Hypertension in BMPR2-Deficient Mice
From the Department of Medicine (L.L., T.K.J., X.Y., N.R., M.S., N.W.M.), University of Cambridge School of Clinical Medicine, Addenbrooke’s and Papworth Hospitals, Cambridge; Institute of Biomedical and Life Sciences (M.R.M., I.M.), Glasgow University; and Department of Genetics and Molecular Medicine (V.J., R.C.T.), School of Medicine, Kings College London, United Kingdom.
Correspondence to Dr Nicholas W. Morrell, Division of Respiratory Medicine, Department of Medicine, Box 157, Addenbrooke’s Hospital, Hills Rd, Cambridge CB2 2QQ, United Kingdom. E-mail nwm23{at}cam.ac.uk
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.
Key Words: pulmonary arterial hypertension • bone morphogenetic protein • serotonin
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