Dataset Information

The role of 5-HT_2B receptors in mitral valvulopathy: bone marrow mobilization of endothelial progenitors.

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.

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.

SUBMITTER: Ayme-Dietrich E

PROVIDER: S-EPMC5680644 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Publications

The role of 5-HT<sub>2B</sub> receptors in mitral valvulopathy: bone marrow mobilization of endothelial progenitors.

Ayme-Dietrich Estelle E Lawson Roland R Côté Francine F de Tapia Claudia C Da Silva Sylvia S Ebel Claudine C Hechler Béatrice B Gachet Christian C Guyonnet Jérome J Rouillard Hélène H Stoltz Jordane J Quentin Emily E Banas Sophie S Daubeuf François F Frossard Nelly N Gasser Bernard B Mazzucotelli Jean-Philippe JP Hermine Olivier O Maroteaux Luc L Monassier Laurent L

British journal of pharmacology 20171015 22

<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>Nordexfenfluramine was infused chronically (28 days) in mi ...[more]

PMID: 28806488

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Project description:The aim of this work was to explore the involvement of 5-HT1B and 5-HT2B receptors (5-HT1BR and 5-HT2BR) in the regulation of free cytoplasmic calcium concentration ([Ca2+]i) in human umbilical vein endothelial cells (HUVEC). We have shown by quantitative PCR analysis, that 5-HT1BR and 5-HT2BR mRNAs levels are almost equal in HUVEC. Immunofluorescent staining demonstrated, that 5-HT1BR and 5-HT2BR are expressed both in plasma membrane and inside the cells. Intracellular 5-HT1BR are localized mainly in the nuclear region, whereas 5-HT2BR receptors are almost evenly distributed in HUVEC. 5-HT, 5-HT1BR agonist CGS12066B, or 5-HT2BR agonist BW723C86 added to HUVEC caused a slight increase in [Ca2+]i, which was much lower than that of histamine, ATP, or SFLLRN, an agonist of protease-activated receptors (PAR1). However, activation of 5-HT1BR with CGS12066B followed by activation of 5-HT2BR with BW723C86 manifested a synergism of response, since several-fold higher rise in [Ca2+]i occurred. CGS12066B caused more than a 5-fold increase in [Ca2+]i rise in HUVEC in response to 5-HT. This 5-HT induced [Ca2+]i rise was abolished by 5-HT2BR antagonist RS127445, indicating that extracellular 5-HT acts through 5-HT2BR. Synergistic [Ca2+]i rise in response to activation of 5-HT1BR and 5-HT2BR persisted in a calcium-free medium. It was suppressed by the phospholipase C inhibitor U73122 and was not inhibited by the ryanodine and NAADP receptors antagonists dantrolene and NED-19. [Ca2+]i measurements in single cells demonstrated that activation of 5-HT2BR alone by BW723C86 caused single asynchronous [Ca2+]i oscillations in 19.8 ± 4.2% (n = 3) of HUVEC that occur with a long delay (66.1 ± 4.3 s, n = 71). On the contrary, histamine causes a simultaneous and almost immediate increase in [Ca2+]i in all the cells. Pre-activation of 5-HT1BR by CGS12066B led to a 3-4 fold increase in the number of HUVEC responding to BW723C86, to synchronization of their responses with a delay shortening, and to the bursts of [Ca2+]i oscillations in addition to single oscillations. In conclusion, to get a full rise of [Ca2+]i in HUVEC in response to 5-HT, simultaneous activation of 5-HT1BR and 5-HT2BR is required. 5-HT causes an increase in [Ca2+]i via 5-HT2BR while 5-HT1BR could be activated by the membrane-permeable agonist CGS12066B. We hypothesized that CGS12066B acts via intracellular 5-HT1BR inaccessible to extracellular 5-HT. Intracellular 5-HT1BR might be activated by 5-HT which could be accumulated in EC under certain pathological conditions.

Dataset Information

The role of 5-HT_2B receptors in mitral valvulopathy: bone marrow mobilization of endothelial progenitors.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

The role of 5-HT<sub>2B</sub> receptors in mitral valvulopathy: bone marrow mobilization of endothelial progenitors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

The role of 5-HT2B receptors in mitral valvulopathy: bone marrow mobilization of endothelial progenitors.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

The role of 5-HT<sub>2B</sub> receptors in mitral valvulopathy: bone marrow mobilization of endothelial progenitors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

The role of 5-HT_2B receptors in mitral valvulopathy: bone marrow mobilization of endothelial progenitors.