ADP receptor P2Y12 is expressed in vascular smooth muscle cells and stimulates contraction in human blood vessels
ADP receptor P2Y12 is expressed in vascular smooth muscle cells and stimulates contraction in human blood vessels
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DOI：
10.1161/01.atv.0000142376.30582.ed
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发表时间：
2004-10-01
影响因子：
8.7
通讯作者：
Erlinge, D
中科院分区：
文献类型：
--
作者：
Wihlborg, AK;Wang, LW;Erlinge, D
目的：ADP通过激活P2Y(12)受体在血小板聚集中发挥重要作用。方法和结果：在人VSMC的P2受体中，P2Y(12)受体的表达水平显著高于其他两种ADP受体(实时定量聚合酶链式反应的P2Y(1)和P2Y(13))。Western blotting显示一条50kD的条带，与血小板中的条带相似。为了通过模拟体内情况来揭示P2Y(12)受体介导的血管收缩，血管被预收缩到亚最大水平。2-MeSADP刺激乳内动脉(IM)、IM分支和小静脉的血管段收缩(E-max=15+/-6%的60 mmol/L K+收缩，pec(50)=5.6+/-0.6，E-max=21+/-1%，pec(50)=6.8+/-0.1，E-max=48+/-9%，pec(50)=6.6+/-0.4)。选择性的P2Y(12)拮抗剂AR-C67085阻断2-MeSADP的收缩。使用氯吡格雷的患者的收缩没有减少，氯吡格雷是一种通过阻断P2Y(12)受体来抑制ADP诱导的血小板聚集的药物。这可能是由于活性氯吡格雷代谢物的高度不稳定性，这种代谢产物永远不会到达全身循环。结论-ADP作用于P2Y(12)受体不仅对血小板活化很重要，而且对血管收缩也有刺激作用。稳定的药物对P2Y(12)受体有拮抗作用，同时影响血小板和VSMC，在预防血栓形成和血管痉挛方面可能具有双重疗效。
Objective - ADP plays an important role in platelet aggregation by activating P2Y(12) receptors. We assessed the hypothesis that P2Y(12) receptors are expressed in vascular smooth muscle cells (VSMC).Methods and Results - P2Y(12) receptor mRNA was found to have a high expression among the P2 receptors in human VSMC, significantly higher than the other 2 ADP receptors (P2Y(1) and P2Y(13), real-time polymerase chain reaction). Western blots gave a band of 50 kD, similar to that in platelets. To unmask a P2Y(12) receptor-mediated vasoconstriction by simulating the in vivo situation, vessels were precontracted to a submaximal level. 2-MeSADP stimulated contractions in vessel segments from internal mammary artery (IM), IM branches and small veins (E-max = 15 +/- 6% of 60 mmol/L K+ contraction, pEC(50) = 5.6 +/- 0.6, E-max = 21 +/- 1%, pEC(50) = 6.8 +/- 0.1, and E-max = 48 +/- 9%, pEC(50) = 6.6 +/- 0.4). The selective P2Y(12) antagonist AR-C67085 blocked 2-MeSADP contractions. The contraction was not reduced in patients using clopidogrel, a drug inhibiting ADP-induced platelet aggregation by blocking the P2Y(12) receptor. This may be explained by the high instability of the active clopidogrel metabolite that never reaches the systemic circulation.Conclusion - ADP acting on P2Y(12) receptors not only is important for platelet activation but also stimulates vasoconstriction. Stable drugs with antagonistic effects on P2Y(12) receptors, affecting both platelets and VSMC, could be of double therapeutic benefit in their prevention of both thrombosis and vasospasm.