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Archives of cardiovascular diseases
Volume 110, n° 1
pages 51-59 (janvier 2017)
Doi : 10.1016/j.acvd.2016.08.002
Received : 24 June 2016 ;  accepted : 19 August 2016
Cardiovascular remodeling and the peripheral serotonergic system
Remodelage cardiovasculaire et système sérotoninergique périphérique
 

Estelle Ayme-Dietrich a, Gaëlle Aubertin-Kirch a, Luc Maroteaux b, Laurent Monassier a,
a Laboratoire de neurobiologie et pharmacologie cardiovasculaire (EA7296), faculté de médecine, fédération de médecine translationnelle, laboratoire de neurobiologie et pharmacologie cardiovasculaire (EA7296), université et centre hospitalier de Strasbourg, 67085 Strasbourg, France 
b Inserm UMR-S 839, institut du Fer-à-Moulin, Sorbonne université, UPMC université Paris 06, 75005 Paris, France 

Corresponding author. Laboratoire de neurobiologie et pharmacologie cardiovasculaire (EA7296), faculté de médecine, 11, rue Humann, 67085 Strasbourg cedex, France.
Summary

Plasma 5-hydroxytryptamine (5-HT; serotonin), released from blood platelets, plays a major role in the human cardiovascular system. Besides the effect of endogenous serotonin, many drugs targeting serotonergic receptors are widely used in the general population (antiobesity agents, antidepressants, antipsychotics, antimigraine agents), and may enhance the cardiovascular risk. Depending on the type of serotonin receptor activated and its location, the use of these compounds triggers acute and chronic effects. The acute cardiovascular response to 5-HT, named the Bezold-Jarish reflex, leads to intense bradycardia associated with atrioventricular block, and involves 5-HT3 , 5-HT1B/1D , 5-HT7 and 5-HT2A/2B receptors. The chronic contribution of 5-HT and its receptors (5-HT4 and 5-HT2A/2B ) in cardiovascular tissue remodeling, with a particular emphasis on cardiac hypertrophy, fibrosis and valve degeneration, will be explored in this review. Finally, through the analysis of the effects of sarpogrelate, some new aspects of 5-HT2A receptor pharmacology in vasomotor tone regulation and the interaction between endothelial and smooth muscle cells will also be discussed. The aim of this review is to emphasize the cardiac side effects caused by serotonin receptor activation, and to highlight their possible prevention by the development of new drugs targeting this system.

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Résumé

La sérotonine (5-hydroxytryptamine ou 5-HT) plasmatique, libérée dans la circulation générale par les plaquettes sanguines, joue un rôle majeur dans le système cardiovasculaire humain. En plus des effets produits par la sérotonine endogène, de nombreux médicaments ciblant les récepteurs sérotoninergiques (antiobésité, antimigraineux, antipsychotiques, antidépresseurs…) sont largement utilisés dans la population générale et pourraient augmenter le risque cardiovasculaire. En fonction du sous-type de récepteur activé et de sa localisation, l’utilisation de ces produits induit des effets aigus et chroniques. L’effet cardiovasculaire aigu du à la sérotonine, appelé réflexe de Bezold-Jarish et conduisant à une bradycardie intense associée à un bloc atrio-ventriculaire, implique les récepteurs sérotoninergiques 5-HT3 , 5-HT1B/1D , 5-HT7  et 5-HT2A/2B . La stimulation chronique des récepteurs 5-HT4  et 5-HT2A/2B conduit au remodelage du tissu cardiovasculaire, et en particulier les aspects d’hypertrophie cardiaque, de fibrose et de dégénérescence valvulaire ont été développés dans cette revue. À travers les effets du sarpogrelate, de nouveaux aspects de la pharmacologie du récepteur 5-HT2A dans la régulation du tonus vasomoteur et l’interaction entre les cellules endothéliales et les cellules musculaires lisses sont aussi discutés. Le but de cette revue est de souligner les effets indésirables cardiovasculaires liés à la stimulation des récepteurs sérotoninergiques périphériques dans le but de les prévenir mais aussi de mettre en avant les possibilités offertes par le développement de nouvelles molécules ciblant ce système.

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Keywords : Serotonin, Cardiac remodeling, Cardiac hypertrophy, Valve degeneration, Fibrosis

Mots clés : Sérotonine, Remodelage cardiaque, Hypertrophie cardiaque, Dégénérescence valvulaire, Fibrose

Abbreviations : 5-HIAA, 5-HT, eNOS, MAO-A, NO, SERT, TGF


Background

Outside the area of migraine and the use of 5-HT1B/1D serotonergic agonists, some recent clinical observations have revived interest in and questions about serotonin (5-hydroxtryptamine [5-HT]) and its receptors in the cardiovascular field. The induction of pulmonary hypertension and cardiac valvulopathy by drugs used in obese patients (fenfluramine/phentermine, benfluorex) or to treat Parkinson's disease (pergolide), raised a question about the cardiovascular risk of compounds targeting some serotonergic receptors. Interestingly, valve lesions induced by these compounds are similar to those observed in the carcinoid heart-cardiac remodeling caused by tumors secreting high amounts of 5-HT. On the other hand, some epidemiologic data have suggested that serotonergic blockers, such as second-generation antipsychotics, may protect the cardiovascular system in schizophrenia. Finally, a link between depression, the use of serotonin selective reuptake inhibitor antidepressants and cardiovascular risk was suggested many years ago.

The aim of this short review is to highlight the contribution of 5-HT and its receptors to cardiovascular tissue remodeling, with a particular emphasis on cardiac hypertrophy, fibrosis and valve degeneration. Some new aspects of serotonergic receptors in blood pressure control will also be discussed. A brief description of the peripheral serotonergic system will be given initially. The deleterious cardiovascular effects of 5-HT and serotonergic agonists are summarized in Figure 1.



Figure 1


Figure 1. 

Deleterious cardiovascular effects of 5-hydroxytryptamine (5-HT; serotonin) and serotonergic agonists. R: receptor.

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Serotonin synthesis, metabolism and effectors

Most (90%) of the 5-HT synthesized in the body comes from the periphery, where it is mainly produced by gut enterochromaffin cells from the essential amino acid, tryptophan, and the limiting enzyme, tryptophan hydroxylase-1; it is then taken up by the serotonin transporter (SERT) in platelets, and stored in dense granula together with calcium and adenosine triphosphate. When released by platelets, 5-HT triggers biological effects through its interaction with membrane receptors; it can also act through intracellular mechanisms involving oxidative stress generation, following its metabolism by mitochondrial monoamine oxidase A (MAO-A) and putative protein serotonylation by transglutaminase-2. The main 5-HT metabolite generated by MAO-A is 5-hydroxyindole acetic acid (5-HIAA). Fifteen 5-HT receptors belonging to seven families have now been identified. The 5-HT3 -ionotropic receptor is a pentameric cationic channel blocked by molecules of the “setron” family. Other receptors are G-protein coupled: Gi-mediated negative regulation of adenylyl cyclase for 5-HT1 and 5-HT5 ; Gs-mediated activation of adenylyl cyclase for 5-HT4 , 5-HT6 and 5-HT7 ; and Gq-mediated stimulation of phospholipase C for the three members of the 5-HT2 sub-family. Most of the receptors are found in cardiovascular tissues, where they contribute to physiological regulation and/or pathological processes (Table 1). Of note, the 5-HT2A receptor expressed at the platelet membrane surface is involved in a positive feedback loop to maintain and stimulate platelet aggregation.

5-HT and its receptors in cardiac hemodynamics, failure and remodeling
5-HT and its receptors in acute cardiovascular responses: from the Bezold-Jarish reflex to heart failure

The contribution of 5-HT to the pathophysiology of the failing heart was suggested many years ago, following the description of the Bezold-Jarish reflex, which is typically intense bradycardia associated with atrioventricular block, 60minutes after an anterior or posterior myocardial infarction; it has been used as a marker of successful thrombolysis, indicating that it occurs at the time of reperfusion [1]. In addition to bradycardia, this reflex is characterized by a drop in blood pressure, a decrease in cardiac contractility and coronary artery vasodilatation.

The Bezold-Jarish reflex can be reproduced by an intravenous bolus injection of 5-HT. The subsequent response occurs in three phases. The first phase is transient, combining bradycardia and a fall in blood pressure; this is caused by the simulation of 5-HT3 receptors localized on afferent parasympathetic nerves that, in turn, block sympathetic neurons at the level of the brainstem. This response can provoke atrioventricular block, and is reversed by atropine. In the second phase, 5-HT triggers an increase in blood pressure as a consequence of 5-HT2A receptor stimulation in the arterial wall, leading to reflex bradycardia. There is also a reduction in the release of catecholamines by the presynaptic stimulation of 5-HT1B/1D receptors. Finally, the third phase is a long-lasting reduction in blood pressure resulting from a ganglionic blockade following 5-HT1B/1D stimulation, and the activation of 5-HT7 receptors localized on smooth muscle cells and of 5-HT2B receptors that drive nitric oxide (NO) release by endothelial cells [2]. Interestingly, continuous 5-HT infusion triggers only the third phase, but reveals tachycardia linked to atrial 5-HT4 receptor stimulation in humans. This response could become relevant in the case of heart failure, where the 5-HT4 receptor appears to be overexpressed.

All these data raise the question of the origin of cardiac 5-HT. In humans, myocardium contains around 0.4μg of 5-HT/g of tissue [3]; its origin is unclear. Local synthesis by tryptophan hydroxylase-2 in autonomic ganglia [4] or capture by SERT from circulating stores have been suggested. Microdialysis experiments in rabbits revealed an increase in myocardial 5-HT during coronary artery occlusion, most of it coming from platelets in a mechanism involving 5-HT2A receptors [5]. This free 5-HT, acutely released at the time of reperfusion, could explain the first phase of the Bezold-Jarish reflex.

5-HT receptors and hemodynamics in the failing heart

Interestingly, the distribution and functional role of serotonergic receptors in the heart follows that of adrenergic receptors. Similarly to the α1-adrenergic subtype, 5-HT2 receptors are classically Gq/diacyl glycerol/inositol trisphosphate-coupled when β1 and 5-HT4 receptors are coupled to the Gs/adenylyl cyclase system [6]. In humans, the 5-HT4 receptor is expressed in atria and ventricles; as with other serotonergic receptors, its level of expression is quite low in a physiological situation, but can increase markedly in case of ventricular dysfunction [7]. The 5-HT4 receptor appears to be a representative of a fetal cardiac gene programme, which is reactivated in heart failure [8]. Without phosphodiesterase inhibition, only sparse effects are obtained following 5-HT4 receptor stimulation, probably because of the rapid withdrawal of cyclic adenosine monophosphate [9]. In case of heart failure, this activity is reduced, revealing a role for these receptors; their stimulation provokes an increase in myocardial contractility and relaxation at a similar concentration to isoproterenol [7]; in some cases it can also trigger arrhythmias [6]. Interestingly, responses involving 5-HT4 receptors do not become desensitized, unlike β-adrenoceptors, and might therefore be used as a compensatory mechanism driving hemodynamic support. This question was studied in a rat model of rapidly progressing cardiac hypertrophy followed by heart failure caused by pressure overload [10]. An increase in 5-HT4 receptor expression was observed from the early steps of hypertrophy, and was maintained in the failing myocardium. This overexpression was correlated to inotropic responses by the natural agonist 5-HT. Therefore, it was tempting to investigate the effect of chronic 5-HT4 receptor blockade in cardiac hypertrophy. The same group investigated the effect of 6 weeks of treatment with the selective 5-HT4 receptor antagonist, piboserod, started 3 days after a myocardial infarction induced by coronary artery ligation in rats [11]. The drug improved cardiac hemodynamics, but no survival study was performed. Nevertheless, all the data obtained on 5-HT4 receptors and piboserod paved the way for a prospective double-blind parallel-group study in patients receiving conventional therapy, with New York Heart Association class II–IV heart failure and left ventricular ejection fraction35%. Patients were randomized to receive either placebo or piboserod 80mg for 24 weeks, including 4 weeks of up-titration. The primary endpoint was left ventricular ejection fraction measured by cardiac magnetic resonance imaging. Piboserod slightly but significantly increased ejection fraction (+1.7%), with a trend towards a greater effect in patients not treated with beta-blockers. These partly disappointing results slowed down an area of research that could restart with atrial fibrillation, a frequently associated problem. 5-HT4a and 5-HT4b receptors are expressed at the level of atria, where they activate adenylyl cyclase through the stimulation of the Gs protein, driving the opening of L-type calcium channels [12, 13]. To our knowledge, all research has now stopped in this field. In the failing heart, part of the positive inotropic response elicited by 5-HT is prevented by the 5-HT2A receptor antagonist, ketanserin [14]. Part of this response could come from phosphorylation of myosin light chain-2, in a similar way to that triggered by α1-adrenergic stimulation [10].

5-HT and its receptors in cardiac remodeling

In this research area, most work is related to 5-HT2A/2B receptors. The 5-HT2A receptor is expressed in both cardiomyocytes and fibroblasts. In aging rats, its expression is increased in left ventricular hypertrophy and dysfunction because of hypertension [15]. Genetic studies failed to show polymorphisms in the 5-HT2A receptor gene in patients with hypertrophic cardiomyopathy of genetic origin or caused by hypertension, but its pharmacological blockade can prevent cardiac hypertrophy induced by transverse aortic constriction in mice [16]. Caveolin-3 [17] and the calcineurin/nuclear factor of activated T cells (NFAT) [18] pathways may be involved in these regulations. This receptor, expressed by non-cardiomyocytes, also appears to be involved in cardiac fibrosis; its activation by platelet extracts induces fibroblast proliferation and transdifferentiation to myofibroblasts, and collagen secretion [19]. Recently, the same team identified serotonergic system activation in patients with aortic stenosis, suggesting that this hormone contributes to the pathophysiology of valve fibrosis and adverse ventricular remodeling [20].

Extensive work has been done on the role of the 5-HT2B receptor subtype in cardiac hypertrophy. In the failing human heart, the 5-HT2B receptor is markedly overexpressed compared with in normal tissue, in which the expression level is very low [21]. Interestingly, we found a correlation between the expression of the receptor and plasma cytokines and norepinephrine. These results confirmed previous studies in mice, where chronic β-adrenergic stimulation induced cardiac hypertrophy and secretion of interleukin-6, tumor necrosis factor-α and interleukin-1β, all of which were prevented by simultaneous treatment with a 5-HT2B receptor blocker or in Htr2B −/− mice [22]; this prevention was also associated with a marked reduction in myocardial oxidative stress [23]. Of note, similar results were obtained in terms of hypertrophy, cytokines and oxidative stress produced by stimulation of AT1-angiotensinergic receptors, without any hemodynamic effect. Taking into account that the receptor is expressed in both cardiomyocytes and non-cardiomyocytes, we addressed the question of the exact cardiac cell type(s) involved in these protections. Mice expressing the receptor only in cardiomyocytes were generated. These animals were fully protected from the deleterious effects of both isoproterenol and angiotensin II infusions, indicating that non-cardiomyocytes are involved in cardioprotection provided by 5-HT2B receptor blockade [21]. This work also demonstrated that the 5-HT2B receptor works as a heterodimer with the AT1-angiotensin receptor [21].

Nevertheless, a direct effect on cardiomyocytes themselves cannot be fully excluded, as serotonin, via the Gq-coupled 5-HT2B receptor, has been shown to protect cardiomyocytes against apoptosis by preventing cytochrome C release and the activation of caspases via cross-talks between phosphatidylinositol-3 kinase/Akt and extracellular signal-regulated kinase 1/2 signaling pathways that can activate nuclear factor-κB and regulate the mitochondrial adenine nucleotide translocator, ANT-1 [24]. Furthermore, after 2 weeks of aortic banding, 5-HT2B receptors were overexpressed at both the messenger ribonucleic acid level and the protein level, and the 5-HT2B receptor antagonist, SB215505, attenuated the overexpression and cardiac hypertrophy [25]. Moreover, in a cardiomyocyte cell culture, 5-HT2B receptor blockade prevented 5-HT- and stretch-induced brain natriuretic peptide secretion by blocking nuclear factor-κB nuclear translocation. Based on these results, we investigated the effects of chronic 5-HT2B receptor blockade by the selective antagonist, RS127445, in aging spontaneously-hypertensive rats showing left ventricular hypertrophy with diastolic dysfunction and a normal ejection fraction [15, 26]. Blocking the 5-HT2B receptor, however, did not reduce cardiac hypertrophy, even if blood pressure was reduced with the calcium channel antagonist, nicardipine, but amplified subendocardial fibrosis. In fact, we pointed out a crucial role for endothelial 5-HT2B receptors in maintaining coronary vasodilatation in hypertensive cardiopathy [15]. Therefore, all these data have revealed the complex effect of 5-HT2B receptors on cardiomyocytes, cardiac fibroblasts and coronary vessels, and their role in regulating cardiac hypertrophy and remodeling in left ventricular dysfunction.

5-HT and its receptors in cardiac valve degeneration
5-HT and the carcinoid heart

Carcinoid heart is the main complication of carcinoid tumors. These tumors, usually localized in the terminal part of gut, secrete high amounts of numerous mediators, including 5-HT, bradykinin and transforming growth factor (TGF)-β1; they are responsible for a syndrome that combines vasomotor flush, diarrhea and asthma [27]. At that stage, most of patients have liver metastases secreting hormones to the right heart and lung. 5-HT is captured and metabolized in this last organ, protecting, at least in part, the left heart and other organs from 5-HT effects. About 50% of patients develop a so-called “carcinoid heart”, characterized by retractile lesions of both tricuspid and pulmonary valves, and cell cushions at the endocardial border of the vena cava and coronary sinus [28]. There is no specificity towards right-side valves because left heart valves can also be affected in case of a right-left shunt [29]. In this cancer, it is considered that about 25% of deaths are caused by cardiac lesions. Of note, some patients can show some electrocardiogram abnormalities. Some of these defects originate from cardiac consequences of the valvulopathy (repolarization problems, right bundle branch block), but sinus tachycardia can be provoked by 5-HT itself through stimulation of the atrial 5-HT4 receptor. Diagnosis can be made by echocardiography and the measurement of 24-hour urinary 5-HIAA. To limit false positives with this measurement, tryptophan-rich food, such as bananas, kiwi fruits, nuts, pineapples and avocados, must be avoided.

At the level of the tricuspid valve, echocardiography shows thickened areas, retractions and sometimes calcifications. In a series including 132 patients with a carcinoid syndrome, Pellikka et al. [30] showed that 74 patients had cardiac lesions (56%): the tricuspid valve was affected in 97% of these patients, and the pulmonary valve was affected in 88%. Only 8% had lesions of the left heart (n =7), five of whom had a patent foramen ovale or lung metastases. Tricuspid lesions usually lead to leaks when the degenerative process provokes insufficiency (88%) and stenosis (53%) at the pulmonary level. From a histological point of view, carcinoid plaques appear to be made by numerous myofibroblasts in a dense extracellular matrix of collagen and glucosaminoglycans. This high content in contractile cells explains the frequently observed leaflet retraction. No work has demonstrated clearly the role of the only 5-HT in this process. There is a correlation between blood 5-HT, urinary 5-HIAA and the occurrence of the carcinoid heart [31]. Nevertheless, we cannot exclude that 5-HT might be a marker of tumor secretion without being the causative mechanism. Experimental studies will be required to demonstrate that only 5-HT blockade obtained by inhibition of its synthesis or antagonism of its receptors can prevent the carcinoid heart. Interestingly, some companies have developed tryptophan hydroxylase-1 inhibitors to prevent diarrhea associated with 5-HT excess. The telotristat etiprate compound, which has been investigated recently for the prevention of the carcinoid syndrome (phase II), with promising results [32], would also be worth testing in cardiopathy.

Serotonergic drugs and valvulopathy

If the pathophysiological contribution of 5-HT in the carcinoid heart is not fully confirmed, the occurrence of drug-induced valvulopathy offers the opportunity to investigate the role of serotonergic receptors in cardiac valve degeneration. This rare but serious side effect has been described with the ergot derivatives, methysergide and ergotamine, and other drugs, such as fenfluramine and 3,4-methylenedioxyamphetamine, the active metabolite of methylenedioxymethamphetamine (MDMA; “ecstasy”). All of these compounds share the pharmacological property of being 5-HT2B receptor agonists [33]. Via activation of this receptor, they elicit an increase in human valvular interstitial cells. Interestingly, Parkinsonian patients show an increased risk of valvulopathy compared with non-Parkinsonian controls. The use of pergolide and cabergoline could explain valve lesions, because both drugs behave as agonists for the 5-HT2B receptor. The effects of drugs activating this receptor could also affect cardiac valve bioprostheses. In a 40-year-old patient taking benfluorex – a drug that is, in part, metabolized into nordexfenfluramine – rapid (4 years) degeneration of the matrix was observed, with lesions highly similar to those observed in the carcinoid heart, showing thickened areas and plaque deposits made by smooth muscle α-actin- and vimentin-positive cells in a glycosaminoglycan matrix [34]. In cardiac valves, whatever the valve considered, 5-HT2A receptor and 5-HT2B receptor overexpression is found, with lower expression of the 5-HT4 subtype and the serotonin transporter, SERT. The contribution of the 5-HT2B subtype is reinforced by the observation that cyproheptadine, an antihistaminic drug blocking 5-HT2B receptors, prevents pergolide-induced valvulopathy in rats [35]. Nevertheless, there are some species differences because, in sheep valvular interstitial cells apparently lacking 5-HT2B receptors, 5-HT induces the mitogen-activated protein kinase Erk phosphorylation and TGF-β1 secretion by stimulating the 5-HT2A subtype [36]. By comparison, the mitogenic effect of ecstasy on human valvular interstitial cells is blocked by the 5-HT2B/2C antagonist, SB206553 [37]. Moreover, 5-HT2B receptor antagonism prevents TGF-β1-induced myofibroblast differentiation [38]. This blockade of the TGF-β1 pathway may use non-canonical signaling, as it prevents p38 mitogen-activated protein kinase phosphorylation instead of SMAD3 phosphorylation [38]. This last effect was obtained in porcine aortic interstitial cells, where a 5-HT2B receptor antagonist prevented the formation of calcified nodules, paving the way for a new pharmacological strategy to prevent cardiac valve degeneration.

Nevertheless, moving further with the hypothesis, this area is lacking relevant experimental models, because 5-HT2B receptor agonists induced only minor remodeling in in vitro organotypic valve cultures, as observed with norfenfluramine in mitral valves [39]. In fact, serotonin acts in a complex pathway involving stretch sensors. In porcine aortic valves, cell proliferation, assessed by BrdU incorporation, is increased by stretch [40]. This effect is slightly potentiated by 5-HT alone, but massive proliferation is obtained when 5-HT cell capture is prevented by the SERT inhibitor, fluoxetine, arguing in favor of receptor-dependent 5-HT effects. The same authors have shown that 5-HT and fluoxetine markedly favor stretch-induced collagen deposition. All these data link 5-HT, 5-HT2B receptors, cell proliferation, collagen synthesis and mechanical stretch in valve remodeling. A last issue to be considered is the possible intracellular effects of 5-HT. This bioamine is captured by cells expressing SERT. After this internalization, it can be metabolized or used as a substrate by transglutaminase-2. This enzyme is involved in numerous cell processes, such as migration and transdifferentiation, particularly of endothelial cells and progenitors. Mechanisms involving this enzyme are not fully understood, but a recent work suggests that serotonylation of glutamine residues by transglutaminase-2 could contribute to matrix remodeling. This serotonylation would participate in some genetic forms of mitral prolapse, such as the X-linked mitral prolapse due to filamin-A mutation [41].

Serotonergic blood pressure regulation and atherosclerosis
Blood pressure control and vasomotion

Central mechanisms of blood pressure control, and the role of 5-HT2 receptors in the control of peripheral vasomotor control will not be discussed; these topics are covered by other reviews [42, 43]. Recent clinical data, obtained from the extensive use of the preferential 5-HT2A antagonist, sarpogrelate, in Asian countries, argue in favor of a role for this receptor in vasomotor control. This drug is used as a platelet antiaggregant, in place of clopidogrel, for people who are unable to activate this prodrug, because of poor metabolism through cytochrome P450 2C19. In dogs exposed to a 30% reduction in basal coronary blood flow in the anterior wall, sarpogrelate increased myocardial 5-HT release and 5-HT1B -mediated dilatation involving endothelial nitric oxide synthase (eNOS) [44]. Similarly, sarpogrelate restored perfusion in an ischemic hindlimb model in diabetic mice, through the stimulation of the eNOS/Akt pathway, involving the 5-HT1B receptor [45]. An effect in the absence of 5-HT is possible due to the inverse agonist action of the drug [46, 47]. In patients with a coronary artery disease, a single 200mg oral dose of sarpogrelate increased basal and maximal (adenosine triphosphate) average peak velocity of coronary blood flow [48]. A similar observation was made in experimental vein grafts [49]. Vasodilation caused by 5-HT-induced 5-HT1B receptor stimulation could explain these effects, but the unmasking of other receptors can also be suggested. In rats chronically treated with sarpogrelate, serotonergic stimulation involving 5-HT7 and 5-HT1D receptors counteracts pressure response elicited by sympathetic nervous system stimulation [50]. Therefore, in some conditions, the 5-HT2A receptor blockade could sensitize smooth muscle cells towards vasodilation triggered by other serotonergic receptors.

Serotonergic mechanisms in vascular remodeling and atherosclerosis

Some new data emphasize the involvement of 5-HT2A receptors in vascular wall remodeling and atherosclerosis. In 2003, Hayashi et al. [51] showed that sarpogrelate can reduce the extent of atherosclerotic deposits in the aorta in parallel with induction of eNOS, in rabbits fed a high-cholesterol diet. Together with the previously described reduction in 5-HT and angiotensin II-induced vascular smooth muscle cell proliferation [52, 53], these chronic effects could encourage trials aimed at preventing vascular remodeling with this compound. This hypothesis is now reinforced in peripheral arterial disease, in which sarpogrelate improves the outcome of symptomatic patients [54], but has still to be demonstrated after endovascular therapy. Retrospective studies have shown a reduction in major clinical endpoints, such as amputation or death from any cause, after endovascular therapy for critical hindlimb ischemia [55]. Moreover, the first preliminary results of a recent prospective study suggest that sarpogrelate plus aspirin is as efficacious as sarpogrelate plus clopidogrel in the prevention of restenosis following femoropopliteal arterial stenting [56]. The reduction of neointimal hyperplasia combined with the improvement in endothelial function by sarpogrelate [57] highly encourage its use in peripheral arterial disease, and emphasize the contribution of this serotonergic receptor in chronic artery disease.

Serotonergic mechanisms and vascular reactivity in metabolic syndrome

Metabolic syndrome is a complex situation, in which patients combine cardiovascular and metabolic features. Of note, 5-HT may contribute to some pathophysiological aspects of the syndrome. In rats, 5-HT increases plasma epinephrine and glucose, making animals insulin resistant through the stimulation of 5-HT2A receptors, as it is blocked by sarpogrelate [58]. This experimental insulin-sensitizing effect of sarpogrelate has been confirmed in diabetic patients [59]. High glucose promotes endothelial dysfunction, and 5-HT has been suggested as a key pathophysiological player in vascular complications of diabetes in the context of metabolic syndrome. When rat aortic rings are incubated in the presence of a high glucose concentration, endothelium-dependent vasodilatation triggered by acetylcholine is reduced, whereas endothelium-independent dilatation induced by a NO donor is unaffected, demonstrating the alteration of endothelial cell function only. Sarpogrelate can restore endothelial NO production and, as a consequence, NO-mediated dilatation [60]. Similarly, in a rat model of type 1 diabetes, sarpogrelate reduced blood glucose and endothelial overexpression of platelet endothelial cell adhesion molecule-1 (PECAM-1) overexpression, therefore limiting 5-HT-induced thrombosis [61]. These data emphasize the role of the 5-HT2A receptor in the regulation of vasomotor tone and the interaction between endothelial and smooth muscle cells. Interestingly, this receptor also affects neointimal proliferation and restenosis following arterial stenting, even if is not expressed by endothelial cells themselves. A paracrine mechanism involving cytokines released by smooth muscle cells or the regulation of the homing of circulating cells can be suggested to explain some of the vascular beneficial effects following 5-HT2A receptor blockade.

Conclusions

From the first description of 5-HT as a serum agent acting on the cardiovascular system, to the most recent discoveries, research into 5-HT and its receptors is still ongoing and has already generated numerous therapeutic drugs: antidepressants acting on 5-HT reuptake; atypical antipsychotics blocking 5-HT2 receptors; 5-HT1B/1D agonists to treat migraine; and 5-HT3 antagonists to prevent nausea. Unfortunately, targeting the 5-HT system also generates cardiac side effects, with drugs activating 5-HT2 receptors, such as fenfluramine, ergot derivatives or pergolide. With 15 receptors, two synthesizing enzymes and one transporter, this system is a significant source of discovery, especially in the cardiovascular field. The 5-HT2A and/or 5-HT2B antagonists could act on endothelial hyperplasia and cardiac valve degeneration. The 5-HT4 antagonists could be investigated for their antiarrhythmic effects, but particular care should be taken with the new 5-HT4 agonists that are currently under development to treat constipation, even if, compared with the old cisapride, they are not human ether-a-gogo related gene (hERG) blockers. Finally, the development of new molecules, such as atypical antipsychotics, including the 5-HT7 antagonist, lurasidone, or the 5-HT2B antagonist, aripiprazole, will reactivate research into these receptors expressed by endothelial cells.

Sources of funding

Luc Maroteaux's work was supported by funds from the Centre national de la recherche scientifique, the Institut national de la santé et de la recherche médicale and the Université Pierre-et-Marie-Curie, and by grants from the Fondation pour la recherche sur le cerveau, the Fondation de France and the Fondation pour la recherche médicale “Équipe FRM DEQ2014039529”. Luc Maroteaux's team is part of the École des neurosciences de Paris île-de-France network and of the Bio-Psy Labex, and, as such, this work was supported by French state funds managed by the Agence nationale de la recherche within the Investissements d’avenir programme under reference ANR-11-IDEX-0004-02.

Disclosure of interest

The authors declare that they have no competing interest.

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