The role of 5-HT2B receptors in mitral valvulopathy: bone marrow mobilization of endothelial progenitors.
Br J Pharmacol
; 174(22): 4123-4139, 2017 Nov.
Article
en En
| MEDLINE
| ID: mdl-28806488
ABSTRACT
BACKGROUND AND PURPOSE:
Valvular heart disease (VHD) is highly prevalent in industrialized countries. Chronic use of anorexigens, amphetamine or ergot derivatives targeting the 5-HT system is associated with VHD. Here, we investigated the contribution of 5-HT receptors in a model of valve degeneration induced by nordexfenfluramine, the main metabolite of the anorexigens, dexfenfluramine and benfluorex. EXPERIMENTALAPPROACH:
Nordexfenfluramine was infused chronically (28 days) in mice ((WT and transgenic Htr2B -/- , Htr2A -/- , and Htr2B/2A -/- ) to induce mitral valve lesions. Bone marrow transplantation was also carried out. Haemodynamics were measured with echocardiography; tissues and cells were analysed by histology, immunocytochemistry, flow cytometry and RT -qPCR. Samples of human prolapsed mitral valves were also analysed. KEYRESULTS:
Chronic treatment of mice with nordexfenfluramine activated 5-HT2B receptors and increased valve thickness and cell density in a thick extracellular matrix, mimicking early steps of mitral valve remodelling. Lesions were prevented by 5-HT2A or 5-HT2B receptor antagonists and in transgenic Htr2B -/- or Htr2A/2B -/- mice. Surprisingly, valve lesions were mainly formed by numerous non-proliferative CD34+ endothelial progenitors. These progenitors originated from bone marrow (BM) as revealed by BM transplantation. The initial steps of mitral valve remodelling involved mobilization of BM-derived CD34+ CD31+ cells by 5-HT2B receptor stimulation. Analysis of human prolapsed mitral valves showing spontaneous degenerative lesions, demonstrated the presence of non-proliferating CD34+ /CD309+ /NOS3+ endothelial progenitors expressing 5-HT2B receptors. CONCLUSIONS AND IMPLICATIONS BM-derived endothelial progenitor cells make a crucial contribution to the remodelling of mitral valve tissue. Our data describe a new and important mechanism underlying human VHD.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Receptor de Serotonina 5-HT2B
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Células Progenitoras Endoteliales
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Enfermedades de las Válvulas Cardíacas
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Válvula Mitral
Límite:
Animals
Idioma:
En
Revista:
Br J Pharmacol
Año:
2017
Tipo del documento:
Article
País de afiliación:
Francia