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The role of 5‐HT 2B receptors in mitral valvulopathy: bone marrow mobilization of endothelial progenitors
Author(s) -
AymeDietrich Estelle,
Lawson Roland,
Côté Francine,
Tapia Claudia,
Da Silva Sylvia,
Ebel Claudine,
Hechler Béatrice,
Gachet Christian,
Guyonnet Jérome,
Rouillard Hélène,
Stoltz Jordane,
Quentin Emily,
Banas Sophie,
Daubeuf François,
Frossard Nelly,
Gasser Bernard,
Mazzucotelli JeanPhilippe,
Hermine Olivier,
Maroteaux Luc,
Monassier Laurent
Publication year - 2017
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13981
Subject(s) - progenitor cell , bone marrow , cd34 , medicine , receptor , extracellular matrix , cd31 , transplantation , endocrinology , pathology , stem cell , microbiology and biotechnology , biology , immunohistochemistry
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. Experimental Approach Nordexfenfluramine was infused chronically (28 days) in mice ((WT and transgenic Htr 2B ‐/‐ , Htr 2A ‐/‐ , and Htr 2B/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. Key Results Chronic treatment of mice with nordexfenfluramine activated 5‐HT 2B 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‐HT 2A or 5‐HT 2B receptor antagonists and in transgenic Htr 2B −/− or Htr 2A/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‐HT 2B 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‐HT 2B 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.