ETA receptor antagonists inhibit intimal smooth muscle cell proliferation in human vessels

Maguire, Janet J.; Yu, Julie C.M.; Davenport, Anthony P.

doi:10.1042/cs103s184s

Cited by 13 publications

(9 citation statements)

References 12 publications

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“…Intriguingly in human coronary arteries we have previously shown that recanalisation of thrombus is characterised by formation of new vessels which show intense endothelial ET-like immunoreactivity with ET A but not ET B receptors on the smooth muscle of recanalised vessels [2]. Crucially, ET antagonists have been shown to block proliferation of smooth muscle in the intimal layer of vessels growing in organ culture [19]. The pathogenesis of CTEPH is complex but one question that arises is how much of the disease progression is driven by changes within the unresolved thrombus in parallel to the vasculopathy in the distal arterial bed.…”

Section: Introductionmentioning

confidence: 95%

Endothelin ET A receptors predominate in chronic thromboembolic pulmonary hypertension

et al. 2016

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AimsEndothelin-1 levels are raised in chronic thromboembolic pulmonary hypertension. Our aim in this study was to identify the presence of endothelin receptors in patients with CTEPH by analysing tissue removed at pulmonary endarterectomy.Main methodsPulmonary endarterectomy tissue cross-sections were analysed using autoradiography with [125I]-ET-1 using ligands selective for ETA or ETB to determine sub-type distribution. The precise cellular localisation of ETA and ETB receptors was determined using selective antisera to both sub-types and compared with haematoxylin and eosin, Elastic Van Gieson and smooth muscle actin labelled sections.Key findingsTwo patterns of ET-1 binding were found. In sections with frequent recanalised channels, ET-1 bound to the smooth muscle cells surrounding the channels. In sections where there was less organised thrombus with no obvious re-canalisation, minimal ET-1 binding was observed. Some contractile type smooth muscle cells not associated with recanalised channels and diffusely spread throughout the PEA material were associated with ET receptor antibody binding on immunohistochemistry. There was a greater expression of the ETA receptor type in the specimens.SignificanceThe presence of ET-1 receptors in the chronic thrombus in proximal CTEPH suggests ET-1 could act not only on the distal vasculopathy in the unobstructed vessels but may also stimulate smooth muscle cell proliferation within chronic clot. The abundance of ET receptors within the tissue provides evidence that the ET pathway is involved in the pathology of chronic thrombus reorganisation leading to CTEPH providing a rationale for the repurposing of ET receptor antagonists in the treatment of this condition.

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Section: Introductionmentioning

confidence: 95%

Endothelin ET A receptors predominate in chronic thromboembolic pulmonary hypertension

et al. 2016

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“…Both mediate vasoconstriction of human smooth muscle cells whilst endothelial ETB receptors mediate vasorelaxation via endothelial nitric oxide synthase (eNOS) [8]. In experimentally induced pulmonary hypertension, the endothelin receptor antagonists diminish or abrogate endothelin-induced smooth muscle cell contraction, hypertrophy, hyperplasia and fibrosis [9][10][11].…”

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confidence: 99%

Endothelin receptor expression in idiopathic pulmonary arterial hypertension: effect of bosentan and epoprostenol treatment

Hall¹,

Davie²,

Klein³

et al. 2011

Eur Respir J

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Endothelin receptor antagonists are used to treat idiopathic pulmonary arterial hypertension (IPAH), but human pulmonary arterial endothelin receptor expression is not well defined. We hypothesised that disease and treatment would modify normal receptor distribution in pulmonary resistance arteries of children.Using immunohistochemistry and semiquantitative analysis, we investigated endothelin receptor subtypes A and B (ETA and ETB, respectively), and endothelial nitric oxide synthase (eNOS) expression in peripheral pulmonary arteries of tissue from untreated children with IPAH (n57), following extended combined bosentan and epoprostenol therapy (n55) and from normal subjects (n55).Clinical, haemodynamic and pathological abnormalities were severe and advanced in all IPAH cases. ETA was detected in pulmonary arterial endothelial cells of all normal and diseased tissue and cultured cells. Endothelial ETA, ETB and eNOS expression was reduced in patent, plexiform and dilatation lesions of untreated cases, but in treated cases, ETA and ETB were normal and eNOS increased. In smooth muscle, ETA expression was reduced in treated cases but ETB expression increased in all arteries of both treated and untreated cases.In summary, ETA is expressed on human pulmonary arterial endothelium. In IPAH, combination treatment with bosentan and epoprostenol had a more marked influence on endothelin receptor expression of endothelial than smooth muscle cells.KEYWORDS: Endothelin receptor antagonists, endothelin receptor A and B, endothelium, paediatric idiopathic pulmonary arterial hypertension, peripheral pulmonary arteries I diopathic pulmonary arterial hypertension (IPAH) is a rare, incurable disorder occurring in both children and adults with a normally formed heart, characterised by irreversible occlusion of small intra-acinar pulmonary resistance arteries with development of plexiform lesions resulting in a sustained increase in pulmonary arterial pressure [1]. Death results from right heart failure. Treatment with prostacyclin, endothelin receptor antagonists and phosphodiesterase inhibitors aims to promote dilatation and reparative remodelling of the pulmonary arteries, and has improved survival and quality of life but is not curative [1]. The only therapeutic option for endstage disease is lung transplantation.The endothelin ET-1 is a potent vasoconstrictor and smooth muscle cell mitogen [2] that is important in the pathobiology of pulmonary arterial hypertension [3]. In humans with IPAH, plasma endothelin levels are elevated [4], endothelin-converting enzyme activity is enhanced [5] and lung expression of endothelin is increased [6]. Its action is mediated principally by two receptors, ETA and ETB [7]. Both mediate vasoconstriction of human smooth muscle cells whilst endothelial ETB receptors mediate vasorelaxation via endothelial nitric oxide synthase (eNOS) [8]. In experimentally induced pulmonary hypertension, the endothelin receptor antagonists diminish or abrogate endothelin-induced smooth muscle cell contract...

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“…Similar to what was described for pulmonary arteries, ET A receptors predominate on proximal regions of coronary arteries, whereas the contribution of ET B increases in distal regions [Dashwood et al, 1998]. Neointima formation in organ cultures of human saphenous vein is also stimulated by ET-1, but it is not clear whether ET B receptors alone are involved [Porter et al, 1998] or if ET A receptors also contribute [Maguire et al, 2002].…”

Section: Cell Proliferation and Fibrosismentioning

confidence: 53%

Endothelin receptors as drug targets in chronic cardiovascular diseases: the rationale for dual antagonism

Clozel¹,

Flores²

2006

Drug Development Research

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Endothelin has been described as the most potent vasoconstrictor known. Recent research shows that it is also a growth factor, a promoter of fibrosis and inflammation, and a key initiator of endothelial dysfunction. Endothelin becomes, therefore, a candidate in the pathogenesis of many chronic cardiovascular and fibrotic diseases, and inhibition of endothelin function is a potential therapeutic approach for those diseases. Endothelin receptor antagonists are now established therapy in the treatment of pulmonary arterial hypertension, and present promising perspectives in diabetic nephropathy, peripheral arterial disease, hypertension, heart failure, and pulmonary diseases. Endothelin binds to two endothelin receptors, ET A and ET B , and their respective roles are actively debated. A major challenge lies in the understanding of what is the preferred profile for new drugs: selective ET A antagonism or dual ET A and ET B receptor antagonism. A number of cardiovascular diseases are characterized by an up-regulation of smooth muscle cell ET B receptors mediating vasoconstriction and proliferation, and a down-regulation of endothelial ET B receptors, as compared to the physiological state, creating a situation where both ET A and ET B receptors contribute to vasoconstriction and remodeling. When these two receptor subtypes co-exist, a cross-talk between them, probably a result of receptor heterodimerization, suggests that dual ET A /ET B receptor antagonism may be necessary to obtain maximal efficacy. Drug Dev. Res. 67:825-834, 2006.

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ETA receptor antagonists inhibit intimal smooth muscle cell proliferation in human vessels

Cited by 13 publications

References 12 publications

Endothelin ET A receptors predominate in chronic thromboembolic pulmonary hypertension

Endothelin ET A receptors predominate in chronic thromboembolic pulmonary hypertension

Endothelin receptor expression in idiopathic pulmonary arterial hypertension: effect of bosentan and epoprostenol treatment

Endothelin receptors as drug targets in chronic cardiovascular diseases: the rationale for dual antagonism

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