Department of Vascular and Endovascular Surgery (T.F., A.B., K.J.K., J.M., J.O., E.K., I.K., N.S., W.I., M.U.W., H.S., M.E.), University Hospital Duesseldorf, Heinrich-Heine University, Germany.
Department of Pharmacology, Experimental Therapy and Toxicology, University Hospital Tuebingen, Germany (M.C.).
Arterioscler Thromb Vasc Biol. 2024 Nov;44(11):2294-2317. doi: 10.1161/ATVBAHA.123.320615. Epub 2024 Aug 29.
Platelets play an important role in cardiovascular and cerebrovascular diseases. Abdominal aortic aneurysm (AAA) is a highly lethal, atherosclerosis-related disease with characteristic features of progressive dilatation of the abdominal aorta and degradation of the vessel wall, accompanied by chronic inflammation. Platelet activation and procoagulant activity play a decisive role in the AAA pathology as they might trigger AAA development in both mice and humans.
The present study investigated the impact of the major platelet collagen receptor GP (platelet glycoprotein) VI in pathophysiological processes underlying AAA initiation and progression. For experimental AAA induction in mice, PPE (porcine pancreatic elastase) and the external PPE model were used.
Genetic deletion of GP VI offered protection of mice against aortic diameter expansion in experimental AAA. Mechanistically, GP VI deficiency resulted in decreased inflammation with reduced infiltration of neutrophils and platelets into the aortic wall. Furthermore, remodeling of the aortic wall was improved in the absence of GP VI, as indicated by reduced MMP (matrix metalloproteinase)-2/9 and OPN (osteopontin) plasma levels and an enhanced α-SMA (α-smooth muscle actin) content within the aortic wall, accompanied by reduced cell apoptosis. Consequently, an elevation in intima/media thickness and elastin content was observed in GP VI-deficient PPE mice, resulting in a significantly reduced aortic diameter expansion and reduced aneurysm incidence. In patients with AAA, enhanced plasma levels of soluble GP VI and fibrin, as well as fibrin accumulation within the intraluminal thrombus might serve as new biomarkers to detect AAA early. Moreover, we hypothesize that GP VI might play a role in procoagulant activity and thrombus stabilization via binding to fibrin.
In conclusion, our results emphasize the potential need for a GP VI-targeted antiplatelet therapy to reduce AAA initiation and progression, as well as to protect patients with AAA from aortic rupture.
血小板在心血管和脑血管疾病中发挥着重要作用。腹主动脉瘤（AAA）是一种高度致命的、与动脉粥样硬化相关的疾病，其特征是腹主动脉进行性扩张和血管壁退化，并伴有慢性炎症。血小板激活和促凝活性在 AAA 病理中起决定性作用，因为它们可能在小鼠和人类中触发 AAA 的发展。
本研究探讨了主要血小板胶原受体 GP（血小板糖蛋白）VI 在 AAA 起始和进展的病理生理过程中的作用。为了在小鼠中进行实验性 AAA 诱导，使用了 PPE（猪胰弹性蛋白酶）和外部 PPE 模型。
GP VI 基因缺失为小鼠提供了对实验性 AAA 中主动脉直径扩张的保护。从机制上讲，GP VI 缺乏导致炎症减少，中性粒细胞和血小板浸润到主动脉壁减少。此外，在缺乏 GP VI 的情况下，主动脉壁的重塑得到改善，表现为 MMP（基质金属蛋白酶）-2/9 和 OPN（骨桥蛋白）血浆水平降低，以及主动脉壁内 α-SMA（α-平滑肌肌动蛋白）含量增加，同时细胞凋亡减少。因此，在缺乏 GP VI 的 PPE 小鼠中观察到内膜/中膜厚度和弹性蛋白含量增加，导致主动脉直径扩张减少和动脉瘤发生率降低。在 AAA 患者中，可溶性 GP VI 和纤维蛋白的血浆水平升高，以及腔内血栓中纤维蛋白的积累，可能作为早期检测 AAA 的新生物标志物。此外，我们假设 GP VI 通过与纤维蛋白结合在促凝活性和血栓稳定中发挥作用。
总之，我们的结果强调了针对 GP VI 的抗血小板治疗的潜在需求，以减少 AAA 的起始和进展，并保护 AAA 患者免受主动脉破裂的影响。
