Blood. 2012 Feb 16;119(7):1772-80. Epub 2011 Dec 20.

Serotonin 5-HT2B receptors are required for bone-marrow contribution to pulmonary arterial hypertension.

Launay JM, Hervé P, Callebert J, Mallat Z, Collet C, Doly S, Belmer A, Diaz SL, Hatia S, Côté F, Humbert M, Maroteaux L.

AP-HP, Hopital Lariboisiere, Service de Biochimie; INSERM U942, Paris, France;

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 questions about their role in disease progression. Independently, serotonin (5-HT) and its receptors have been identified as contributors to the PAH pathogenesis. We hypothesized that one of these receptors, the 5-HT(2B) receptor, is involved in bone-marrow stem cell mobilization that participate to the development of PAH and pulmonary vascular remodeling. A first study revealed expression of 5-HT(2B) receptors by circulating c-kit(+) precursor cells, while mice lacking 5-HT(2B) receptors showed alterations in platelets and monocyte-macrophages number and in myeloid lineages of bone-marrow. Strikingly, mice with restricted expression of 5-HT(2B) receptors on bone-marrow cells developed hypoxia- or monocrotaline-induced increase in pulmonary pressure and vascular remodeling, while 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.

PMID:22186990