Impact of platelet-red blood cell interactions on thrombosis and abdominal aortic aneurysm formation: Mechanisms and consequences

血小板-红细胞相互作用对血栓形成和腹主动脉瘤形成的影响：机制和后果

• 批准号: 440966856
• 负责人: Professorin Dr. Margitta Elvers
• 金额: --
• 依托单位: Klinik für Gefäß- und Endovaskularchirurgie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/440966856?language=en
• 关键词: Impact; platelet; red; blood; cell

Red blood cells (RBCs) influence rheology, and release ADP, ATP and nitric oxide suggesting a role for RBCs in hemostasis and thrombosis. Recently, we have shown that a direct cell interaction between platelets and RBCs via the Fas ligand (FasL)-FasR (CD95) pathway induces the externalization of phosphatidylserine (PS) and thus the formation of a pro-coagulant surface at the RBC membrane. Inhibition or genetic deletion of either FasL or FasR resulted in reduced PS exposure of RBCs and platelets, decreased thrombin generation and reduced thrombus formation in vitro and protection against arterial and venous thrombosis in vivo. In surgical specimens of patients after thrombectomy, direct cell contacts of platelets and RBCs via FasL-FasR were demonstrated. In new preliminary studies, we were able to provide initial evidence that the platelet integrin αIIbβ3 (fibrinogen receptor) serves as a potential ligand for FasR at the RBC membrane. Furthermore, we identified a potential new mechanism via CD36 that regulates PS exposure at the RBC membrane probably via binding to platelet released thrombospondin-1 (TSP-1). Early experiments provide evidence for an impact of platelet-RBC interactions in abdominal aortic aneurysm (AAA) in addition to effects on venous and arterial thrombosis. AAA is frequently characterized by the formation of an intraluminal thrombus (ILT) accompanied by hypoxia within the aortic wall and high thrombin plasma levels. Data from our lab showed migration of platelets and RBCs into the abdominal aortic wall of mice with experimental AAA and reduced progression of AAA in platelet-depleted mice. Moreover, enhanced PS exposure at the platelet and RBC membrane was measured in patients with AAA.To date, the pathways and proteins that link platelet activation and thrombin generation to extracellular matrix (ECM) degradation and AAA progression are largely unknown. Moreover, we believe that different mechanisms of platelet-RBC interactions are responsible for thrombin generation in vascular diseases with thrombotic complications. We hypothesize that RBCs modulate platelet activation and thrombus formation in arterial thrombosis and AAA via different signaling pathways according to the availability of oxygen. Therefore we want to experimentally follow three major objectives in the current proposal. First, we want to identify and characterize new cellular mechanisms of platelet-RBC interactions in hemostasis and thrombosis under normoxia and hypoxia. Second, we want to validate the relevance of platelet-RBC interactions in vascular diseases in experimental mice including arterial thrombosis and AAA. Third, we will analyze the mechanisms of platelet-RBC interactions in patients with AAA as a first translational approach.

红细胞 (RBC) 影响流变学，并释放 ADP、ATP 和一氧化氮，表明红细胞在止血和血栓形成中发挥作用。最近，我们发现血小板和红细胞之间通过 Fas 配体 (FasL)-FasR (CD95) 途径的直接细胞相互作用诱导磷脂酰丝氨酸 (PS) 外化，从而在红细胞膜上形成促凝表面。 FasL或FasR的抑制或基因缺失导致红细胞和血小板的PS暴露减少，体外凝血酶生成减少和血栓形成减少，体内防止动脉和静脉血栓形成。在血栓切除术后患者的手术标本中，证实了血小板和红细胞通过 FasL-FasR 的直接细胞接触。 在新的初步研究中，我们能够提供初步证据，证明血小板整合素 αIIbβ3（纤维蛋白原受体）是红细胞膜上 FasR 的潜在配体。此外，我们通过 CD36 发现了一种潜在的新机制，可能通过与血小板释放的血小板反应蛋白-1 (TSP-1) 结合来调节红细胞膜上的 PS 暴露。早期实验提供了证据，证明血小板-红细胞相互作用除了对静脉和动脉血栓形成有影响外，还对腹主动脉瘤 (AAA) 产生影响。 AAA 的常见特征是腔内血栓 (ILT) 的形成，并伴有主动脉壁内缺氧和高凝血酶血浆水平。我们实验室的数据显示，血小板和红细胞迁移到实验性 AAA 小鼠的腹主动脉壁中，并减少了血小板耗尽小鼠的 AAA 进展。此外，在 AAA 患者中测量了血小板和红细胞膜处 PS 暴露的增强。迄今为止，将血小板活化和凝血酶生成与细胞外基质 (ECM) 降解和 AAA 进展联系起来的途径和蛋白质在很大程度上尚不清楚。此外，我们认为血小板-红细胞相互作用的不同机制导致了伴有血栓并发症的血管疾病中凝血酶的产生。我们假设红细胞根据氧气的可用性通过不同的信号通路调节动脉血栓形成和 AAA 中的血小板活化和血栓形成。因此，我们希望通过实验来遵循当前提案中的三个主要目标。首先，我们想要鉴定和表征常氧和缺氧下血小板-红细胞相互作用在止血和血栓形成中的新细胞机制。其次，我们想要验证血小板-红细胞相互作用与实验小鼠血管疾病（包括动脉血栓形成和 AAA）的相关性。第三，我们将分析 AAA 患者血小板-红细胞相互作用的机制，作为第一种转化方法。