Serotonin increases susceptibility to pulmonary hypertension in BMPR2-deficient mice.
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.
Long
Lu
L
Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Cambridge, United Kingdom.
MacLean
Margaret R
MR
Jeffery
Trina K
TK
Morecroft
Ian
I
Yang
Xudong
X
Rudarakanchana
Nung
N
Southwood
Mark
M
James
Victoria
V
Trembath
Richard C
RC
Morrell
Nicholas W
NW
D000818:Animals; D055396:Bone Morphogenetic Protein 2; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000502:physiology*; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004198:Disease Susceptibility; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000209:etiology*; D000860:Hypoxia / Q000503:physiopathology; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D011985:Receptors, Serotonin / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D012333:RNA, Messenger; D011985:Receptors, Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D012701:Serotonin; D048049:Extracellular Signal-Regulated MAP Kinases; D052006:Bone Morphogenetic Protein Receptors, Type II