Pharmacological characterization of nucleotide P2Y receptors on endothelial cells of the mouse aorta

Guns, Pieter-Jan; Korda, A.; Crauwels, Herta; Assche, Tim Van; Robaye, Bernard; Boeynaems, Jean‐Marie; Bult, Hidde

doi:10.1038/sj.bjp.0706326

Cited by 75 publications

(88 citation statements)

References 34 publications

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“…2 This receptor has been shown to contribute to endothelium-dependent relaxation through nitric oxide and prostacyclin release. 16,17,34 However, the function of the P2Y 1 receptor in endothelial cells is largely unknown. Several findings indicate that adenine nucleotides may contribute to an inflammatory state of the endothelium.…”

Section: Discussionmentioning

confidence: 99%

“…9,[12][13][14] Hence, this receptor could represent an interesting target for new antiplatelet compounds. 7,15 The endothelial P2Y 1 receptor contributes, like other P2 receptor subtypes, to nucleotide-induced relaxation 16,17 and was recently shown also to be involved in human endothelial cell migration. 18 The role of P2Y 1 in leukocytes is less well established.…”

Section: Clinical Perspective P 763mentioning

confidence: 99%

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Reduced Atherosclerotic Lesions in P2Y ₁ /Apolipoprotein E Double-Knockout Mice

et al. 2008

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Background— The P2Y 1 receptor plays a key role in arterial thrombosis and is widely expressed in many cell types involved in atherosclerosis. The aim of this study was to evaluate its potential involvement in the development of atherosclerotic lesions. Methods and Results— Apolipoprotein E–deficient ( ApoE −/− ) and P2Y 1 −/− / ApoE −/− mice were maintained on regular chow for 17 or 30 weeks before analysis of atherosclerotic lesions. At 17 weeks, lesions in the aortic sinus and entire aorta were smaller in P2Y 1 −/− / ApoE −/− compared with those in ApoE −/− animals. At 30 weeks, the aortic sinus lesions in P2Y 1 −/− / ApoE −/− mice were still diminished in size and displayed reduced inflammation, reflected by decreased macrophage infiltration and diminished VCAM-1 immunostaining, compared with those in ApoE −/− mice. They also had a lower smooth muscle cell content. Unexpectedly, bone marrow transplantation showed that the absence of the P2Y 1 receptor in blood cells only led to no significant modification of the lesion compared with control ApoE −/− reconstituted animals. Conversely, the absence of the P2Y 1 receptor except in blood cells resulted in a reduction in lesion size similar to that in control P2Y 1 −/− / ApoE −/− reconstituted mice, pointing to a role of non–hematopoietic-derived P2Y 1 receptors, most likely the endothelial or smooth muscle cell P2Y 1 receptors. In addition, although this was not statistically significant, plasma cholesterol levels were consistently decreased in P2Y 1 −/− animals, suggesting that a modification of lipid metabolism could be responsible for the observed phenotype. Conclusion— The P2Y 1 receptor contributes to atherosclerosis, primarily through its role in non–hematopoietic-derived cells.

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Section: Discussionmentioning

confidence: 99%

Section: Clinical Perspective P 763mentioning

confidence: 99%

Reduced Atherosclerotic Lesions in P2Y ₁ /Apolipoprotein E Double-Knockout Mice

et al. 2008

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“…Well before cloning any of the purinergic or nucleotide receptors, Van Coevorden and Boeynaems showed that micromolar concentrations of ADP stimulated the release of prostaglandin (PG)I 2 from cultured bovine aortic endothelial cells. 19 Recently, it has been reported that ADP induces endothelium-dependent relaxation of several arteries, including rat mesenteric artery, 20 guinea pig, and mouse aorta 21,22 via NO release. These studies suggested that ADP could exert 2 opposite actions on platelet aggregation in vivo: a direct stimulation and an indirect inhibition mediated by PGI 2 and NO released from the endothelium.…”

Section: Shen and Dicorleto Adp Signaling And Endothelial Cell Migratmentioning

confidence: 99%

ADP Stimulates Human Endothelial Cell Migration via P2Y ₁ Nucleotide Receptor–Mediated Mitogen-Activated Protein Kinase Pathways

Shen

DiCorleto

2008

Circulation Research

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Abstract-Extensive research on the role of ADP in platelet activation led to the design of new anti-thrombotic drugs, such as clopidogrel (Plavix; sanofi-aventis); however, very little is known about the ADP-preferring nucleotide receptors (P2Y 1 , P2Y 12 , and P2Y 13 ) in endothelium. Here, we show that ADP stimulates migration of cultured human umbilical vein endothelial cells (HUVECs) in both Boyden chamber and in vitro wound repair assays. This promigratory effect was mimicked by 2-MeSADP, but not by AMP, and was inhibited by MRS2179 (P2Y 1 receptor antagonist) but not by AR-C69931MX (P2Y 12/13 receptor antagonist). RT-PCR revealed abundant P2Y 1 , barely detectable P2Y 12 , and absent P2Y 13 receptor message in these cells. In addition, both ADP and 2-MeSADP, but not AMP, activated the mitogen-activated protein kinase pathways as evidenced by increased phosphorylation of extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK), and p38 kinase. ADP also stimulated phosphorylation of p90RSK, a downstream substrate of phosphorylated ERK1/2, and induced phosphorylation of such transcription factors downstream of the JNK and p38 pathways as c-Jun and activating transcription factor-2. These signaling events were inhibited by MRS2179 but not by AR-C69931MX. Furthermore, blockade of the ERK or JNK pathways by U0126 and SP600125, respectively, abolished ADP-and 2-MeSADP-stimulated HUVEC migration. However, inhibition of the p38 pathway by SB203580 partially suppressed ADP-and 2-MeSADP-induced HUVEC migration. We conclude that ADP promotes human endothelial cell migration by activating P2Y 1 receptor-mediated MAPK pathways, possibly contributing to reendothelialization and angiogenesis after vascular injury. V ascular endothelial cell migration and proliferation are vital in many physiological and pathological processes, including organ development, angiogenesis, and healing of the injured endothelium. 1,2 Numerous factors produced within the vascular wall or from the circulating blood can stimulate migration and/or proliferation of endothelial cells through their cognate receptors, which are either receptor tyrosine kinases, such as vascular endothelial growth factor (VEGF), or G protein-coupled receptors, such as thrombin. 2,3 In addition to these well-established factors, extracellular nucleotides are relatively newly defined vasoactive substances in the vasculature. 4 -6 ATP and UTP stimulate vascular smooth muscle constriction and proliferation 5,6 ; however, in intact arteries, nucleotides usually cause endotheliumdependent relaxation, 5 suggesting that endothelium has 1 or more functional nucleotide receptors. Indeed, among the 8 cloned P2Y nucleotide receptors (P2Y 1,2,4,6,11,12,13,14 ), 5 a previous study in human vascular endothelial cells showed significant level of P2Y 1 , P2Y 2 , and P2Y 11 receptor mRNAs. The expression levels of the newly cloned P2Y 12 , 13 , 14 receptors were not investigated. 7 It also has been shown that stimulation of the P2Y 2 receptor by ATP or UTP in cultur...

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“…[19] Adenosine diphosphate has been shown to induce vasoconstriction via P2Y12 receptors; however, it is also believed to cause arterial relaxation by increasing the synthesis of endothelium-derived nitric oxide (NO). [19][20][21] Thus, the effect of ADP-mediated pathways on the endothelium is currently unclear. [22] Clopidogrel has been reported to exhibit vasomodulatory activity [23] and direct endothelial effects independent from antiplatelet actions, [24] which are still not fully understood.…”

Section: Discussionmentioning

confidence: 99%

The effects of clopidogrel, acetyl salicylic acid and tirofiban on acetylcholine-induced dilation in rat thoracic aorta segments

Özkısacık¹,

Discigil²,

Kurtoğlu³

et al. 2012

Turk Gogus Kalp Dama

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Amaç: Bu çalışmada, asetilsalisilik asit (ASA), klopidogrel ve tirofiban gibi antitrombositer ajanların sıçan torasik aort segmentinde asetilkolin (ACh) ile uyarılan gevşeme yanıt-ları üzerine olan etkileri araştırıldı. Ça lış ma pla nı: Yirmi sekiz adet ağırlıkları 250-300 g arasında olan Wistar-albino türü yetişkin erkek sıçan çalışmaya alındı. Sıçanlar randomize olarak dört gruba ayrıldı: ASA grubu (n=7), klopidogrel grubu (n=7), tirofiban grubu (n=7) ve kontrol grubu (n=7). Deneyden 12 saat önce intraperitoneal (İP) ASA (1.5 mg/kg) veya klopidogrel (1 mg/kg) enjeksiyonları yapıldı. Tirofiban grubunda, 150 μgr/kg tirofiban İP deneyden 1 ve 12 saat önce olmak üzere, iki kez verildi. Kontrol grubundaki sıçanlara herhangi bir ilaç verilmedi. Sıçanlar dekapite edildikten sonra torasik aort segmentleri çıkartıldı ve oksijenize Krebs çözeltisi içinde organ banyosuna asıldı ve aort halkalarında asetilkolin ile uyarılan gevşeme yanıtının doza bağımlı değişimleri incelendi. Bul gu lar: Asetilkolinin en düşük molar konsantrasyonu (10-9) ile elde edilen gevşeme yanıtının ASA (%94.3±3.3) ve klopidogrel (%94.6±3.1) grubunda kontrol (%86.7±8.1) grubuna göre azalmış olduğu bulundu (p<0.05). Daha yük-sek asetilkolin konsantrasyonlarında ise, tüm gruplarda gevşeme yanıtlarının benzer olduğu gözlemlendi. So nuç: Asetilsalisilik asit ve klopidogrel tedavilerinin sonucunda endotel aracılı gevşeme yanıtında hafif bir gecikme ortaya çıkmış ve tirofibanın belirgin bir etkisi olmamıştır. Bu bulgular ASA ve klopidogrelin endotel aracılı vazodilatasyon üzerinde sınırlı bir etkisi olabileceğini düşündürmektedir.Anah tar söz cük ler: Asetilsalisilik asit; klopidogrel; endotel; tirofiban. Background:In this article, we aimed to investigate the effects of antithrombotic agents, including acetyl salicylic acid (ASA), clopidogrel, and tirofiban on the acetylcholine (ACh)-induced dilation responses in rat thoracic aorta segments. Methods: Twenty-eight Wistar albino male rats weighing between 250-300 g were included in the study. The rats were randomly divided into four groups: the ASA group (n=7), the clopidogrel group (n=7), the tirofiban group (n=7), and the control group (n=7). Intraperitoneal (IP) injection of ASA (1.5 mg/kg) or clopidogrel (1 mg/kg) was administered 12 hours before the experiment. In the tirofiban group, 150 μgr/kg tirofiban IP was given twice at one and 12 hours before the experiment. The rats in the control group did not receive any medication. After the rats were decapitated, the segments of the thoracic aorta were removed and suspended in an oxygenated Krebs solution in a tissue bath, and the dose dependency in the responses to the ACh-induced dilation in the aortic rings were studied. Results:The dilation responses of the aortic rings to ACh in the lowest molar concentration (10-9) were found to be reduced in the ASA (94.3%±3.3) and clopidogrel (94.6%±3.1) groups when compared with the control group (86.7%±8.1) (p<0.05). The responses to higher concentrations of ACh were observed to be similar in all of the groups....

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Pharmacological characterization of nucleotide P2Y receptors on endothelial cells of the mouse aorta

Cited by 75 publications

References 34 publications

Reduced Atherosclerotic Lesions in P2Y ₁ /Apolipoprotein E Double-Knockout Mice

Reduced Atherosclerotic Lesions in P2Y ₁ /Apolipoprotein E Double-Knockout Mice

ADP Stimulates Human Endothelial Cell Migration via P2Y ₁ Nucleotide Receptor–Mediated Mitogen-Activated Protein Kinase Pathways

The effects of clopidogrel, acetyl salicylic acid and tirofiban on acetylcholine-induced dilation in rat thoracic aorta segments

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Pharmacological characterization of nucleotide P2Y receptors on endothelial cells of the mouse aorta

Cited by 75 publications

References 34 publications

Reduced Atherosclerotic Lesions in P2Y 1 /Apolipoprotein E Double-Knockout Mice

Reduced Atherosclerotic Lesions in P2Y 1 /Apolipoprotein E Double-Knockout Mice

ADP Stimulates Human Endothelial Cell Migration via P2Y 1 Nucleotide Receptor–Mediated Mitogen-Activated Protein Kinase Pathways

The effects of clopidogrel, acetyl salicylic acid and tirofiban on acetylcholine-induced dilation in rat thoracic aorta segments

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Product

Resources

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Reduced Atherosclerotic Lesions in P2Y ₁ /Apolipoprotein E Double-Knockout Mice

Reduced Atherosclerotic Lesions in P2Y ₁ /Apolipoprotein E Double-Knockout Mice

ADP Stimulates Human Endothelial Cell Migration via P2Y ₁ Nucleotide Receptor–Mediated Mitogen-Activated Protein Kinase Pathways