Serotonin and Cardiovascular Diseases
2019, Elsevier eBooks
https://doi.org/10.1016/B978-0-12-800050-2.00012-7Abstract
Serotonergic dysfunction is mainly associated with neuropsychiatric and cardiovascular disorders but has also been linked with many other pathological conditions. This review provides an overview of the recent pharmacological developments involving 5hydroxytryptamine (5-HT; serotonin), released from blood platelets, in the human cardiovascular system. The acute cardiovascular response to serotonin, named the Bezold-Jarish reflex, leads to intense bradycardia associated with atrioventricular block, and involves 5-HT 3 , 5-HT 1B , 5-HT 7 and 5-HT 2A/2B receptors. The contribution of serotonin and its receptors (5-HT 4 and 5-HT 2A/2B ) in cardiac development, in cardiovascular tissue remodeling, with a particular emphasis on cardiac hypertrophy, fibrosis and failure, in valve degeneration, is explored in this review. Some new aspects of 5-HT 1B , 5-HT 7 and 5-HT 2A/2B receptors in vasomotor tone regulation and the interaction between endothelial and smooth muscle cells are also be discussed. As well, serotonin, its transporter, 5-HT 1B , and 5-HT 2B receptors participation in pulmonary hypertension and pulmonary vascular remodeling are presented. Finally, the contribution of bone marrow derived endothelial progenitors in the pathogenesis of pulmonary hypertension and interactions with bone morphogenic protein type 2 receptor signaling are highlighted. The aim of this review is thus to emphasize the vascular, cardiac and pulmonary effects caused by serotonin receptor activation, and to highlight their possible prevention by the development of new drugs targeting this system. cardiovascular regulation. In periphery, this mediator contributes to control many cardiovascular functions since, in addition to effects on platelet aggregation and hematopoietic stem cells differentiation, serotonin can modulate blood pressure, heart rate and respiration. Finally, it has a major pathophysiological role in metastatic neuroendocrine carcinoid tumors. Carcinoid tumors are neuroendocrine tumors originating from enterochromaffin cells that develop within the digestive tract and secrete large amounts of serotonin . The cardiovascular functions of serotonin, often unrecognized, have recently been re-evaluated in particular in cerebral and pulmonary circulatory beds with development of "serotonergic" drugs for treatment of migraines and likely in a near future in primary pulmonary arterial hypertension (PAH) and valvular heart diseases (VHD). It may be surprising that a unique mediator possesses so many different functions. This diversity can be explained by the fact that serotonin acts through numerous receptors. , working on guinea pig ileum, proposed that serotonin acts, on two pharmacologically different receptors, M (muscarin-sensitive) and D (dibenzylinsensitive) receptors located on smooth muscles and neurons respectively. During early 90s, identification of serotonin receptor genes has progressed considerably with gene cloning and sequencing techniques. It now appears that there are 15 different receptor genes, divided into four subtypes: 5-HT 1/5 , 5-HT 2 , 5-HT 3 , and 5-HT 4/6/7 . These receptors are grouped according to their intracellular coupling mode. 5-HT 3 receptors are ion channels whereas all others are G-protein coupled receptors: Gi proteins for 5-HT 1/5 , Gs for 5-HT 4/6/7 and finally Gq for 5-HT 2 . Subfamilies have been distinguished within these categories. Thus, for example, there are three members in 5-HT 2 receptors (5-HT 2A , 2B , 2C ). In this chapter, we will present current state of knowledge about roles of serotonin, its transporter and its receptors in physiology and pathology of cardiovascular system. Serotonin is present at early stages of embryogenesis and is synthesized during zygotic cleavages, gastrulation and neurulation . Serotonin appears necessary for the formation of heart: immunolabeling studies with antibody directed against serotonin revealed that the myocardium of mice embryos (E8-11) grown in the presence of serotonin can take up this mediator avidly. Thereafter, uptake decreases to be restricted to endocardial cushions. Thymidine incorporation experiments show that serotonin, reuptake inhibitors, fluoxetine or sertraline, inhibit proliferation of cardiac mesenchyme, endocardium and myocardium especially at E9 (before cushion formation). Serotonin therefore participates in cardiac morphogenesis before and during formation of endocardial cushions (see below). In mice, expression of 5-HT 2A and 5-HT 2B receptors is observed during active phases of morphogenesis in neuroepithelium, notochord, somites, neural crest cells, craniofacial mesenchyme, myocardium and endocardial cushions, dental germs, hair follicles, cartilage and striated muscles . In mouse embryo culture experiments, antagonists of high affinity for 5-HT 2B receptor such as ritanserin (but not ketanserin, a 5-HT 2A preferential antagonist) cause morphological deficits in cephalic, cardiac and neural tube regions. These treatments interfere with migration of neural crest cells and cause their apoptosis . With regard to heart formation, these treatments lead to an abnormal organization of sarcomeres of subepicardial layer and to the absence of myocardial trabeculation.
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