title: Serotonin 5-HT2B receptors are required for bone-marrow contribution to pulmonary arterial hypertension.
abstract: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by lung endothelial dysfunction and vascular remodeling. Recently, bone marrow progenitor cells have been localized to PAH lungs, raising the question of their role in disease progression. Independently, serotonin (5-HT) and its receptors have been identified as contributors to the PAH pathogenesis. We hypothesized that 1 of these receptors, 5-HT(2B), is involved in bone marrow stem cell mobilization that participates in the development of PAH and pulmonary vascular remodeling. A first study revealed expression of 5-HT(2B) receptors by circulating c-kit(+) precursor cells, whereas mice lacking 5-HT(2B) receptors showed alterations in platelets and monocyte-macrophage numbers, and in myeloid lineages of bone marrow. Strikingly, mice with restricted expression of 5-HT(2B) receptors in bone marrow cells developed hypoxia or monocrotaline-induced increase in pulmonary pressure and vascular remodeling, whereas restricted elimination of 5-HT(2B) receptors on bone marrow cells confers a complete resistance. Moreover, ex vivo culture of human CD34(+) or mice c-kit(+) progenitor cells in the presence of a 5-HT(2B) receptor antagonist resulted in altered myeloid differentiation potential. Thus, we demonstrate that activation of 5-HT(2B) receptors on bone marrow lineage progenitors is critical for the development of PAH.
authors.affiliation: Inserm U942, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Lariboisière, Service de Biochimie, Paris, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Launay
authors.forename: Philippe
authors.initials: P
authors.lastname: Hervé
authors.forename: Jacques
authors.initials: J
authors.lastname: Callebert
authors.forename: Ziad
authors.initials: Z
authors.lastname: Mallat
authors.forename: Corinne
authors.initials: C
authors.lastname: Collet
authors.forename: Stéphane
authors.initials: S
authors.lastname: Doly
authors.forename: Arnauld
authors.initials: A
authors.lastname: Belmer
authors.forename: Silvina L
authors.initials: SL
authors.lastname: Diaz
authors.forename: Sarah
authors.initials: S
authors.lastname: Hatia
authors.forename: Francine
authors.initials: F
authors.lastname: Côté
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.forename: Luc
authors.initials: L
authors.lastname: Maroteaux
mesh_terms: D000818:Animals; D001769:Blood / Q000378:metabolism; D001774:Blood Chemical Analysis; D001853:Bone Marrow / Q000378:metabolism / Q000502:physiology*; D001854:Bone Marrow Cells / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D044403:Receptor, Serotonin, 5-HT2B / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D044403:Receptor, Serotonin, 5-HT2B; D019009:Proto-Oncogene Proteins c-kit