Further evidence that 5‐HT‐induced relaxation of pig pulmonary artery is mediated by endothelial 5‐HT<sub>2B</sub> receptors

Glusa, Erika; Pertz, Heinz H.

doi:10.1038/sj.bjp.0703341

Cited by 91 publications

(53 citation statements)

References 33 publications

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“…4). Such a result regarding 5-HT 2B receptors may not be very surprising since it has been previously shown that 5-HT 2B receptors induce a relaxation mediated by endothelial 5-HT 2B receptors in pig pulmonary arteries [21].…”

Section: Effect Of 5-ht On Camentioning

confidence: 87%

Signalling pathways involved in the contractile response to 5-HT in the human pulmonary artery

Rodat-Despoix¹,

Aires²,

Ducret³

et al. 2009

Eur Respir J

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Serotonin (5-hydroxytryptamine; 5-HT) is a potent pulmonary vasoconstrictor and mitogenic agent whose plasma level is increased in pulmonary hypertensive patients. Thus, we explored the signalling pathways involved in the contractile response to 5-HT in human pulmonary arteries (HPAs).Intact and b-escin permeabilised rings from HPAs mounted in an organ bath system were used to assess both tension and myofilament Ca 2+ -sensitisation. KEYWORDS: Calcium, contraction, human pulmonary artery, myofilament calcium sensitivity, 5-HT S erotonin (5-hydroxytryptamine; 5-HT) is mainly stored in the platelets but is also locally released in the lung by pulmonary neuroendocrine cells, neuroepithelial bodies and pulmonary arterial endothelial cells [1][2][3]. 5-HT is a potent pulmonary vasoconstrictor whose high circulating concentration is clinically associated with pulmonary arterial hypertension (PAH), an often fatal disease. In animal models of PAH, 5-HT-induced hyperreactivity and mitogenic effects have been reported in pulmonary arteries [4,5]. In human pulmonary arteries (HPAs), while numerous studies have explored the role of 5-HT in vascular remodelling associated with smooth muscle hyperplasia [6,7], few studies have been performed on the contractile effect of 5-HT [8,9]. Nevertheless, 5-HT 1B , 5-HT 2A and 5-HT 2B receptors have been detected in HPA, and the contractile effect of 5-HT appeared to be mainly mediated by the 5-HT 1B receptors and also by the 5-HT 2A receptors [6,[8][9][10][11][12]. Despite the fact that pulmonary arterial vasoconstriction is an important early component of PAH, the current knowledge about transduction pathways involved in the 5-HTinduced vasoreactivity remains incomplete for HPAs.Owing to the low availability of human tissue, we previously studied the contractile response to 5-HT in rat intrapulmonary arteries and we demonstrated that there were regional differences in 5-HT-induced contraction [13]. Since calcium is essential for smooth muscle contraction, we addressed the relative contribution of calcium pools involved in the vasoreactivity to 5-HT. In small vessels, 5-HT activates voltage-independent calcium channels to a larger extent than it does voltage-dependent calcium channels (L-type calcium channels) [5,[13][14][15]. Calcium release from intracellular calcium stores (sarcoplasmic reticulum) also contributes to 5-HT-induced contraction in rat pulmonary arteries [13][14][15]. Studies from other groups have been performed on calcium signalling and ion channels in cultured human

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Section: Effect Of 5-ht On Camentioning

confidence: 87%

Signalling pathways involved in the contractile response to 5-HT in the human pulmonary artery

Rodat-Despoix¹,

Aires²,

Ducret³

et al. 2009

Eur Respir J

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“…5-HTR 2B is expressed in human PAEC and stimulates calcium release (47). 5-HTR 2B elicits a reversible endothelium-dependent relaxation of pulmonary arteries in pigs, associated with an increase in cyclic GMP (11), through coupling to NO signaling pathway (30). Loss of function of 5-HTR 2B has been incriminated in fenfluramine-associated PAH (4).…”

Section: Expression Of Genes Related To Nf-b Pathway In Crpstimulatedmentioning

confidence: 99%

NF-κB pathway is involved in CRP-induced effects on pulmonary arterial endothelial cells in chronic thromboembolic pulmonary hypertension

Wynants

Vengethasamy

Ronisz

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Wynants M, Vengethasamy L, Ronisz A, Meyns B, Delcroix M, Quarck R. NF-B pathway is involved in CRP-induced effects on pulmonary arterial endothelial cells in chronic thromboembolic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 305: L934-L942, 2013. First published October 4, 2013 doi:10.1152/ajplung.00034.2013.-Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by thrombofibrotic obstruction of proximal pulmonary arteries. The cellular and molecular mechanisms underlying the pathogenesis remain incompletely understood, although we recently evidenced the potential involvement of the inflammatory marker C-reactive protein (CRP). We aimed to investigate the intracellular mechanisms induced by CRP in proximal pulmonary arterial endothelial cells (PAEC). PAEC were isolated from vascular material obtained during pulmonary endarterectomy. RNA was extracted from CRP-stimulated PAEC, and first-stand cDNA was generated. A RT 2 profiler PCR Array was used to evaluate the expression of 84 key genes related to NF-B-mediated signal transduction. CRP-induced NF-B activation was studied. The effects of pyrrolidine-dithio-carbamate ammonium (PDTC), an inhibitor of the NF-B pathway, were investigated on CRP-induced adhesion of monocytes to PAEC, adhesion molecule expression, endothelin-1 (ET-1), interleukin-6 (IL-6), and von Willebrand factor (vWF) secretion. Compared with nonstimulated PAEC, serotonin receptor 2B was downregulated by 25%, inhibitor of NF-B kinase subunit epsilon (IKBKE) by 30%, and toll-like receptor-4 and -6 by 18 and 39%, respectively, in CRP-stimulated PAEC. The transcription factor FOS was threefold upregulated. CRP induced RelA/NF-Bp65 phosphorylation. PDTC dose dependently inhibited the adhesion of monocytes to CRP-stimulated PAEC. PDTC also inhibited the CRP-induced expression of ICAM-1 at the surface of PAEC. PDTC impaired the secretion of ET-1 by 18% and tended to inhibit the secretion of IL-6 by CRP-stimulated PAEC by 46%. PDTC did not inhibit the CRP-induced secretion of vWF. These results suggest an involvement of the NF-B pathway in mediating different effects of CRP on proximal CTEPH-PAEC. C-reactive protein; endothelial cells; NF-B; chronic thromboembolic pulmonary hypertension CHRONIC THROMBOEMBOLIC PULMONARY hypertension (CTEPH) is a severe cause of pulmonary hypertension characterized by an obliteration of proximal pulmonary arteries by intraluminal thrombi and fibrous stenosis. Pulmonary embolism, either as single or recurrent episodes, is thought to be the initiating event followed by progressive pulmonary vascular remodeling. Vascular disobliteration by pulmonary endarterectomy (PEA) is the preferred treatment for CTEPH patients (38).Knowledge of the physiopathology of CTEPH remains incomplete. Proximal lesions share similarities with atherosclerotic plaques, including media thickening and neointima formation (1). Risk factors for CTEPH include size of the initial thrombus, elevated factor VIII, circulating phospholipid antibodies, and fibrinogen intrinsic ...

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“…30,31) Atypical 5-HT receptors that mediate endothelium-dependent relaxation have been detected in numerous blood vessels. While some were initially classified as 5-HT 1 -like (a heterogeneous group that is currently subdivided into 5-HT 1B , 5-HT 1D , 5-HT 7 ) 32) (pig coronary arteries, 33) porcine vena cava 34) ), others may be tentatively classified as subtypes of the 5-HT 2 type (rabbit jugular vein, 35) rat jugular vein, 5,25) porcine pulmonary arteries 3,4,36) ). Taking this into account as well as the presence of mRNA for 5-HT 2B and 5-HT 1B in rat aorta, 2) we have focused on the pharmacological characterization of these types of receptors.…”

Section: Discussionmentioning

confidence: 99%

“…Apart from this receptor, 5-HT 2B , 5-HT 1B , and 5-HT 7 mRNAs have been detected in this tissue 2) by polymerase chain reaction (PCR) techniques. The corresponding receptors mediate different responses in the isolated preparations where they have been functionally described: the 5-HT 2B receptor has been located in the endothelium of pig pulmonary artery 3,4) and rat jugular vein, 5) mediating relaxation. It has also been proposed that this receptor in smooth muscle mediates vasoconstriction in the mesenteric artery of mineralocorticoid hypertensive rats.…”

mentioning

confidence: 99%

Functional Characterization of Serotonin Receptors in Rat Isolated Aorta.

Villazón¹,

Padín²,

Cadavid³

et al. 2002

Biological & Pharmaceutical Bulletin

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The complex actions of serotonin (5-HT) on blood vessels is attributed to interactions with a multiplicity of specific 5-HT receptors located in smooth muscle and endothelium, sometimes mediating opposite effects.In the case of rat aorta, at least the 5-HT 2A receptor is functionally present 1) and it mediates potent vasoconstriction with a relatively low affinity for 5-HT. Apart from this receptor, 5-HT 2B , 5-HT 1B , and 5-HT 7 mRNAs have been detected in this tissue 2) by polymerase chain reaction (PCR) techniques. The corresponding receptors mediate different responses in the isolated preparations where they have been functionally described: the 5-HT 2B receptor has been located in the endothelium of pig pulmonary artery 3,4) and rat jugular vein, 5) mediating relaxation. It has also been proposed that this receptor in smooth muscle mediates vasoconstriction in the mesenteric artery of mineralocorticoid hypertensive rats.6,7) The 5-HT 1B receptor has been described in a variety of tissues (for example, human coronary arteries, 8) rabbit epicardial coronary arteries, 9) human temporal artery, 10) human and bovine cerebral arteries 11) ) and mediates vasoconstriction when located in smooth muscle or relaxation when in endothelium. The 5-HT 7 receptor is located in smooth muscle, where it induces vasorelaxation (for a review see 12) ) in many preparations such as canine coronary and cerebral arteries, 13,14) dog basilar artery and cerebral blood vessels, 15,16) and cynomolgus monkey isolated jugular vein. 17)In addition, functional effects of some of these receptors appear to be related to the preconstriction of the tissue. Thus contractile synergism between 5-HT and other vasoconstrictor substances has been observed in peripheral and cerebrovascular blood vessels (for a review see 18,19) ). For example, in guinea pig isolated iliac arteries 5-HT 1 -like silent receptor appears only in the presence of vascular tone.20) The same phenomenon has been described in bovine isolated pulmonary arteries 21) and in rabbit isolated mesenteric arteries, 22) where preconstriction of the tissue with different contractile agents revealed potent vasoconstrictory effects of 5-HT. In rat aorta, a mutual amplification in contractile responses by simultaneous activation of a 1 and 5-HT 2 receptors has been described. 23) This phenomenon may play an important role in certain pathological states such as hypertension, peripheral vascular disease, and coronary spasm.18) The importance of preconstriction is even greater in the case of relaxant receptors because normally preconstriction is needed for a relaxant response to occur.Taking all these data together, the effects of 5-HT on blood vessels are complex and dependent on the anatomical location of the receptors and on additional factors such as preconstriction of the tissue with a non-5-HT receptor agonist that could unmask previously inactive or "silent" 5-HT receptor subtypes. In the preparation we have studied, rat aorta, the presence of mRNA for different 5-HT receptors (5-HT 2B...

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Further evidence that 5‐HT‐induced relaxation of pig pulmonary artery is mediated by endothelial 5‐HT_2B receptors

Cited by 91 publications

References 33 publications

Signalling pathways involved in the contractile response to 5-HT in the human pulmonary artery

Signalling pathways involved in the contractile response to 5-HT in the human pulmonary artery

NF-κB pathway is involved in CRP-induced effects on pulmonary arterial endothelial cells in chronic thromboembolic pulmonary hypertension

Functional Characterization of Serotonin Receptors in Rat Isolated Aorta.

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Further evidence that 5‐HT‐induced relaxation of pig pulmonary artery is mediated by endothelial 5‐HT2B receptors

Cited by 91 publications

References 33 publications

Signalling pathways involved in the contractile response to 5-HT in the human pulmonary artery

Signalling pathways involved in the contractile response to 5-HT in the human pulmonary artery

NF-κB pathway is involved in CRP-induced effects on pulmonary arterial endothelial cells in chronic thromboembolic pulmonary hypertension

Functional Characterization of Serotonin Receptors in Rat Isolated Aorta.

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Further evidence that 5‐HT‐induced relaxation of pig pulmonary artery is mediated by endothelial 5‐HT_2B receptors