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Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension

Abstract

Primary pulmonary hypertension is a progressive and often fatal disorder in humans that results from an increase in pulmonary blood pressure associated with abnormal vascular proliferation. Dexfenfluramine increases the risk of pulmonary hypertension in humans, and its active metabolite is a selective serotonin 5-hydroxytryptamine 2B (5-HT2B) receptor agonist. Thus, we investigated the contribution of the 5-HT2B receptor to the pathogenesis of pulmonary hypertension. Using the chronic-hypoxic-mouse model of pulmonary hypertension, we found that the hypoxia-dependent increase in pulmonary blood pressure and lung remodeling are associated with an increase in vascular proliferation, elastase activity and transforming growth factor-β levels, and that these parameters are potentiated by dexfenfluramine treatment. In contrast, hypoxic mice with genetically or pharmacologically inactive 5-HT2B receptors manifested no change in any of these parameters. In both humans and mice, pulmonary hypertension is associated with a substantial increase in 5-HT2B receptor expression in pulmonary arteries. These data show that activation of 5-HT2B receptors is a limiting step in the development of pulmonary hypertension.

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Figure 1: Requirement of the 5-HT2BR for hypoxia-induced RVSP and vascular muscularization.
Figure 2: Requirement of the 5-HT2BR for hypoxia-induced lung remodeling.
Figure 3: Requirement of 5-HT2BRs for lung-remodeling factors but not for acute vasoconstriction.
Figure 4: Hypoxia increases 5-HT2BR expression in lungs.
Figure 5: Model of 5-HT2BR-dependent hypoxia-induced RVSP in mice.

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Acknowledgements

We thank P. Hickel for technical assistance: J. Odillard for animal care: V. Mutel, Pr. J.-L. Laplanche and M. Mark for critical reading of the manuscript and for discussions: M. Pando and S. Brooks for English corrections: V. Mutel and D. McNamara for the gift of RS-127445: and F. Mentré and F. Godmard for statistical expertise. This work has been supported by funds from the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the Hôpital Universitaire de Strasbourg and the Université Louis Pasteur, and by grants from the Fondation de France and the Association pour la Recherche contre le Cancer.

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Correspondence to L. Maroteaux.

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Launay, JM., Hervé, P., Peoc'h, K. et al. Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension. Nat Med 8, 1129–1135 (2002). https://doi.org/10.1038/nm764

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