Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
J Intern Med. 2019 Jan;285(1):59-74. doi: 10.1111/joim.12821. Epub 2018 Sep 7.
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.
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.
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.
Inhibition of intraplaque haemorrhage by controlling neovessels maturation holds promise to improve plaque stability.
斑块血管生成与动脉粥样硬化病变生长、斑块不稳定和不良临床结局有关。斑块血管生成是一个自然发生的过程，以满足血管壁对氧气和营养的不断增加的需求。然而，不成熟的、未成熟的斑块新生血管是渗漏的，并导致斑块内出血。
阻断 VEGFR2 可使斑块新生血管形成的失控过程正常化，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，并随后增加斑块稳定性。
在人颈动脉和静脉移植的动脉粥样硬化病变中，渗漏的斑块新生血管和斑块内出血与 VEGF/VEGFR2 和血管生成素共定位。利用接受供体腔静脉间置于颈动脉的高脂血症 ApoE3*Leiden 小鼠，我们证明在 t28 时，动脉粥样硬化静脉移植病变与缺氧、Hif1α 和 Sdf1 上调有关。局部给予 VEGF 可增加斑块血管生成。在该模型中，VEGFR2 阻断导致斑块内出血减少 44%，漏出的红细胞减少 80%，与对照组相比。体内 VEGFR2 阻断导致静脉移植病变大小减少 32%，病变更稳定，巨噬细胞含量减少 30%，胶原增加 54%，平滑肌细胞含量增加 123%。VEGF、血管生成素-2 表达水平降低和 Connexin 40 表达水平升高表明静脉移植物中斑块新生血管成熟度增加。在主动脉环测定中，VEGFR2 阻断可增加毛细血管芽周细胞的覆盖。
通过控制新生血管的成熟来抑制斑块内出血有望改善斑块稳定性。
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