<br>阻断血管内皮生长因子受体 2 可通过斑块新生血管的正常化来抑制斑块内出血。,Journal of Internal Medicine

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阻断血管内皮生长因子受体 2 可通过斑块新生血管的正常化来抑制斑块内出血。
Journal of Internal Medicine ( IF 9.0 ) Pub Date : 2018-09-07 , DOI: 10.1111/joim.12821
M R de Vries _{1,

2} , L Parma _{1,

2} , H A B Peters _{1,

2} , A Schepers ₁ , J F Hamming ₁ , J W Jukema ₃ , M J T H Goumans ₄ , L Guo ₅ , A V Finn ₅ , R Virmani ₅ , C K Ozaki ₆ , P H A Quax _{1,

2}

Affiliation

背景斑块血管生成与动脉粥样硬化病变生长、斑块不稳定性和阴性临床结果相关。斑块血管生成是满足血管壁不断增长的氧气和营养需求的自然发生的过程。然而，形成不充分、未成熟的斑块新血管会渗漏并导致斑块内出血。目的阻断 VEGFR2 使斑块新血管形成的不受限制的过程正常化，并诱导新生血管成熟，从而防止斑块内出血和炎症细胞流入斑块，从而增加斑块稳定性。方法和结果在人颈动脉和静脉移植物动脉粥样硬化病变中，渗漏斑块新生血管和斑块内出血与 VEGF/VEGFR2 和血管生成素共定位。使用在颈动脉中接受供体腔静脉介入的高胆固醇血症 ApoE3*Leiden 小鼠，我们证明 t28 时的动脉粥样硬化静脉移植物病变与缺氧、Hif1α 和 Sdf1 上调有关。局部 VEGF 给药导致斑块血管生成增加。与对照组相比，该模型中的 VEGFR2 阻断导致斑块内出血显着减少 44%，外渗红细胞减少 80%。体内 VEGFR2 阻断导致静脉移植物尺寸减少 32%，病变更稳定，巨噬细胞含量显着减少 (30%)，胶原蛋白 (54%) 和平滑肌细胞含量 (123%) 增加。 VEGF、血管生成素-2 的显着降低和连接蛋白 40 表达水平的增加表明静脉移植物中斑块新血管的成熟增加。主动脉环试验中的 VEGFR2 阻断显示毛细血管芽的周细胞覆盖增加。结论通过控制新生血管成熟来抑制斑块内出血有望改善斑块稳定性。

"点击查看英文标题和摘要"

Blockade of vascular endothelial growth factor receptor 2 inhibits intraplaque haemorrhage by normalization of plaque neovessels.

BACKGROUND Plaque angiogenesis is associated with atherosclerotic lesion growth, plaque instability and negative clinical outcome. Plaque angiogenesis is a natural occurring process to fulfil the increasing demand of oxygen and nourishment of the vessel wall. However, inadequate formed, immature plaque neovessels are leaky and cause intraplaque haemorrhage. OBJECTIVE Blockade of VEGFR2 normalizes the unbridled process of plaque neovessel formation and induces maturation of nascent vessels resulting in prevention of intraplaque haemorrhage and influx of inflammatory cells into the plaque and subsequently increases plaque stability. METHODS AND RESULTS In human carotid and vein graft atherosclerotic lesions, leaky plaque neovessels and intraplaque haemorrhage co-localize with VEGF/VEGFR2 and angiopoietins. Using hypercholesterolaemic ApoE3*Leiden mice that received a donor caval vein interposition in the carotid artery, we demonstrate that atherosclerotic vein graft lesions at t28 are associated with hypoxia, Hif1α and Sdf1 up-regulation. Local VEGF administration results in increased plaque angiogenesis. VEGFR2 blockade in this model results in a significant 44% decrease in intraplaque haemorrhage and 80% less extravasated erythrocytes compared to controls. VEGFR2 blockade in vivo results in a 32% of reduction in vein graft size and more stable lesions with significantly reduced macrophage content (30%), and increased collagen (54%) and smooth muscle cell content (123%). Significant decreased VEGF, angiopoietin-2 and increased Connexin 40 expression levels demonstrate increased plaque neovessel maturation in the vein grafts. VEGFR2 blockade in an aortic ring assay showed increased pericyte coverage of the capillary sprouts. CONCLUSION Inhibition of intraplaque haemorrhage by controlling neovessels maturation holds promise to improve plaque stability.

更新日期：2018-09-17

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