Platelets as Biosensors and Mediators of Aortic Aneurysm Growth

项目摘要 无症状腹主动脉瘤(Aaa)可在出院时进展为破裂。 死亡率高达90%。AAA生长加速与血小板活化和血小板有关 动脉瘤节段的聚集物(血栓)。抗血小板药物可能限制AAA的生长和破裂 风险。对这些观察结果的机械解释从未被阐明过。此项目构建 我们发现AAA患者的血小板通过选择性表面过度激活 此外，抗血小板药物阿司匹林可以部分抑制AAA的生长和破裂。这 提示了血小板活化和动脉瘤形成之间的新联系，并提示阿司匹林可能 不是最好的抗血小板药物来抑制。动脉瘤的生长。使用体外系统 动脉瘤性动脉血流紊乱(湍流)的重述，嗅觉的定位 血小板膜表面受体是抑制AAA的新靶点 成长。在暴露于湍流中的腹主动脉瘤患者的血小板中发现这一途径 是我们对血小板如何机械感知和反应的概念上的进步 到他们的外部环境。因此，血小板作为循环生物传感器出现，释放蛋白质 它们是区分快速增长的动脉瘤和缓慢增长的动脉瘤的有用的生物标志物。这个项目提供了 第一种治疗AAA的药物疗法的承诺。

Project Summary Asymptomatic abdominal aortic aneurysms (AAA) can progress to rupture with an out-of-hospital mortality of 90%. Accelerated AAA growth is associated with platelet activation and platelet aggregates (thrombi) in aneurysmal segments. Antiplatelet drugs may limit AAA growth and rupture risk. A mechanistic explanation for these observations has never been elucidated. This project builds upon our discovery that platelets from patients with AAA are hyperactivated through selective surface receptors and that the antiplatelet drug aspirin partially inhibits AAA growth and rupture. This suggests a new link between platelet activation and aneurysm development, and implies aspirin may not be the best antiplatelet drug to suppress. aneurysm growth. Using an ex vivo system to recapitulate disturbed (turbulent) blood flow in aneurysmal arteries, localization of an olfactory receptor on the surface of the platelet membrane is a new and promising target to suppresses AAA growth. Discovering this pathway in platelets from patients with AAA exposed to turbulent blood flow is a conceptual advancement in our understanding of how platelets mechanically sense and respond to their external environment. Platelets therefore emerge as circulating biosensors, releasing proteins that are useful biomarkers for distinguishing fast from slow-growing aneurysms. This project offers the promise of the first medical therapy to treat AAA.