LPA1 receptor-mediated thromboxane A2 release is responsible for lysophosphatidic acid-induced vascular smooth muscle contraction
LPA1 receptor-mediated thromboxane A2 release is responsible for lysophosphatidic acid-induced vascular smooth muscle contraction
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DOI：
10.1096/fj.201600735r
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发表时间：
2017-04-01
期刊：
影响因子：
4.8
通讯作者：
Benyo, Zoltan
中科院分区：
文献类型：
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作者：
Dancs, Peter Tibor;Ruisanchez, Eva;Benyo, Zoltan
溶血磷脂酸（LPA）最近被认为是一种内皮依赖性血管扩张剂，但一些证据表明它也可能刺激血管平滑肌细胞（VSMC），从而有助于血管调节和重塑。在本研究中，在小鼠主动脉VSMC中检测到所有6种LPA受体基因的mRNA表达，其中LPA(1)、LPA(2)、LPA(4)和LPA(6)水平最高。在去内皮的胸主动脉 (TA) 和腹主动脉 (AA) 段中，1-油酰-LPA 和 LPA(1-3) 激动剂 VPC31143 诱导剂量依赖性血管收缩。 VPC31143 诱导的 AA 收缩对百日咳毒素 (PTX)、LPA(1&3) 拮抗剂 Ki16425 以及 LPA(1) 基因删除敏感，但对 LPA(2) 基因删除或焦磷酸二酰基甘油对 LPA(3) 的抑制不敏感。令人惊讶的是，在缺乏环氧合酶-1 [COX1 敲除 (KO)] 或血栓素前列腺素 (TP) 受体 (TPKO) 的血管中，血管收缩也减弱。 VPC31143 增加了野生型、TP-KO 和 LPA(2)-KO 小鼠 TA 中血栓素 A(2)(TXA(2)) 的释放，但不增加 LPA(1)-KO 或 COX1-KO 小鼠中的血栓素 A(2)(TXA(2)) 释放，PTX 阻断了这种作用。我们的研究结果表明，LPA 通过 LPA(1)、G(i) 和 COX1 依赖性自分泌/旁分泌 TXA(2) 释放和随后的 TP 激活介导 VSMC 中的血管收缩。我们提出，这种新发现的 LPA/LPA(1) 和 TXA(2)/TP 通路之间的相互作用在血管调节、止血、血栓形成和血管重塑中发挥着重要作用。-Dancs, P. T., Ruisanchez, E., Balogh, A., Panta, C. R., Miklos, Z., N" using, R. M., Aoki, J., Chun, J., Offermanns，S.，Tigyi，G.，Beny'o，Z.LPA（1）受体介导的血栓素A（2）释放负责溶血磷脂酸诱导的血管平滑肌收缩。
Lysophosphatidic acid (LPA) has been recognized recently as an endothelium-dependent vasodilator, but several lines of evidence indicate that it may also stimulate vascular smooth muscle cells (VSMCs), thereby contributing to vasoregulation and remodeling. In the present study, mRNA expression of all 6 LPA receptor genes was detected in murine aortic VSMCs, with the highest levels of LPA(1), LPA(2), LPA(4), and LPA(6). In endothelium-denuded thoracic aorta (TA) and abdominal aorta (AA) segments, 1-oleoyl-LPA and the LPA(1-3) agonist VPC31143 induced dose-dependent vasoconstriction. VPC31143-induced AA contraction was sensitive to pertussis toxin (PTX), the LPA(1&3) antagonist Ki16425, and genetic deletion of LPA(1) but not that of LPA(2) or inhibition of LPA(3), by diacylglycerol pyrophosphate. Surprisingly, vasoconstriction was also diminished in vessels lacking cyclooxygenase-1 [COX1 knockout (KO)] or the thromboxane prostanoid (TP) receptor (TPKO). VPC31143 increased thromboxane A(2)(TXA(2)) release from TA of wild-type, TP-KO, and LPA(2)-KO mice but not from LPA(1)-KO or COX1-KO mice, and PTX blocked this effect. Our findings indicate that LPA causes vasoconstriction in VSMCs, mediated by LPA(1)-, G(i)-, and COX1-dependent autocrine/paracrine TXA(2) release and consequent TP activation. We propose that this new-found interaction between the LPA/LPA(1) and TXA(2)/TP pathways plays significant roles in vasoregulation, hemostasis, thrombosis, and vascular remodeling.-Dancs, P. T., Ruisanchez, E., Balogh, A., Panta, C. R., Miklos, Z., N " using, R. M., Aoki, J., Chun, J., Offermanns, S., Tigyi, G., Beny ' o, Z. LPA(1) receptor-mediated thromboxane A(2) release is responsible for lysophosphatidic acid-induced vascular smooth muscle contraction.