Endothelial Cell-Specific Deletion of P2Y2 Receptor Promotes Plaque Stability in Atherosclerosis-Susceptible ApoE-Null Mice.
Endothelial Cell-Specific Deletion of P2Y2 Receptor Promotes Plaque Stability in Atherosclerosis-Susceptible ApoE-Null Mice.
复制标题
P2Y2受体的内皮细胞特异性缺失促进了动脉粥样硬化易感的Apoe-Null小鼠的斑块稳定性。
DOI：
10.1161/atvbaha.116.308561
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发表时间：
2017-01
期刊：
影响因子：
--
通讯作者：
Seye CI
中科院分区：
文献类型：
--
作者：
Chen X;Qian S;Hoggatt A;Tang H;Hacker TA;Obukhov AG;Herring PB;Seye CI
核苷酸P2 Y2受体（P2 Y2 R）通过增加内皮细胞（EC）中血管细胞粘附分子（VCAM）-1的表达而促进血管炎症，并且整体P2 Y2 R缺乏可防止ApoE−/−小鼠中脂肪条纹的形成。由于P2 Y2 R在血管细胞中广泛表达，我们研究了内皮细胞P2 Y2 R在动脉粥样硬化发病机制中的作用。EC特异性P2 Y2 R缺陷型小鼠通过使VE钙粘蛋白5-Cre小鼠与P2 Y2 R“floxed”小鼠交配而产生。内皮细胞P2 Y2 R缺陷降低eNOS活性，并显着改变ATP和UTP诱导的血管舒张，而不影响血管舒张反应乙酰胆碱。遥测血压和超声心动图测量结果表明，EC特异性P2 Y2 R缺陷小鼠没有发生高血压。我们通过将EC特异性P2 Y2 R敲除小鼠与ApoE−/−背景杂交，研究了内皮细胞P2 Y2 R在动脉粥样硬化病变发展中的作用，并在喂食标准饲料25周后评价了病变发展。组织病理学检查表明，在EC特异性P2 Y2 R缺陷型Apoe-/-小鼠中，主动脉窦和整个主动脉的动脉粥样硬化病变减少，巨噬细胞浸润减少，平滑肌细胞和胶原蛋白含量增加，导致内皮下纤维帽形成。在EC特异性P2 Y2 R缺陷型ApoE−/−小鼠的动脉粥样硬化病变中，基质金属蛋白酶（MMP）-2的表达和蛋白水解活性显著降低。此外，EC特异性P2 Y2 R缺陷抑制NO的产生，导致SMC迁移出主动脉外植体的显着增加。EC特异性P2 Y2 R缺陷通过受损的巨噬细胞浸润与MMP-2活性降低和SMC迁移增加共同作用，降低ApoE−/−小鼠的动脉粥样硬化负荷并促进斑块稳定性。
Nucleotide P2Y2 receptor (P2Y2R) contributes to vascular inflammation by increasing vascular cell adhesion molecule (VCAM)-1 expression in endothelial cells (EC), and global P2Y2R deficiency prevents fatty streak formation in ApoE−/− mice. Since P2Y2R is ubiquitously expressed in vascular cells, we investigated the contribution of endothelial P2Y2R in the pathogenesis of atherosclerosis. EC-specific P2Y2R-deficient mice were generated by breeding VEcadherin5-Cre mice with the P2Y2R “floxed” mice. Endothelial P2Y2R deficiency reduced eNOS activity and significantly altered ATP-and UTP-induced vasorelaxation without affecting vasodilatory responses to acetylcholine. Telemetric blood pressure and echocardiography measurements indicated that EC-specific P2Y2R-deficient mice did not develop hypertension. We investigated the role of endothelial P2Y2R in the development of atherosclerotic lesions by crossing the EC-specific P2Y2R knockout mice onto an ApoE−/− background and evaluated lesion development after feeding a standard chow diet for 25 weeks. Histopathological examination demonstrated reduced atherosclerotic lesions in the aortic sinus and entire aorta, decreased macrophage infiltration and increased smooth muscle cell and collagen content leading to the formation of a subendothelial fibrous cap in EC-specific P2Y2R-deficient ApoE−/− mice. Expression and proteolytic activity of matrix metalloproteinase (MMP)-2 was significantly reduced in atherosclerotic lesions from EC-specific P2Y2R-deficient ApoE−/− mice. Furthermore, EC-specific P2Y2R deficiency inhibited NO production leading to significant increase in SMC migration out of aortic explants. EC-specific P2Y2R-deficiency reduces atherosclerotic burden and promotes plaque stability in ApoE−/− mice through impaired macrophage infiltration acting together with reduced MMP-2 activity and increased SMC migration.