Rôle des plaquettes dans la formation et la rupture des anévrysmes intracrâniens

Intracranial aneurysms (IAs) are localized dilatations or bulges in cerebral artery walls, predominantly affecting the circle of Willis. These vascular abnormalities remain a significant challenge in neurovascular medicine, with rupture prediction and development of less invasive treatments being primary concerns. While the inflammatory nature of IAs is well-established, the thrombus formation and platelets in this disease has been consistently observed but poorly understood. Platelets are crucial in maintaining vascular integrity and modulating inflammation, making them potential key actors in IA pathophysiology, characterized by loss of vascular integrity and chronic inflammation. This study aimed to elucidate the role of platelets in IA formation and development. We implemented in the laboratory a well-defined murine model of IA to decipher platelet mechanisms in IA development. To better understand the role of platelet in IA development, we developed a novel histological grading system incorporating multiple parameters, including wall thickness and vessel dilation. This grading system allowed us to uncover changes in neutrophil, macrophage, and platelet recruitment throughout the different stages of aneurysm development. Our study demonstrated, for the first time, a pre-activated state of platelets in mice with IAs. :as characterized by an increase of platelet activation marker, P-selectin expression, enhanced interactions with neutrophils, and increased sensitivity to stimuli. Surprisingly, mice deficient for platelet activation receptor exhibited a distinct pre-activated state without elevated P-selectin expression but maintained enhanced interaction with neutrophils, suggesting sophisticated compensation among these receptors in IA context. We observed a significant decrease in the plasma of a key platelet cytokine, platelet factor 4 (PF4) in IA mice, indicating its active involvement in IA pathophysiology. Interestingly, PF4 KO mice displayed a worse survival rate compared to WT mice and presented a higher incidence of aneurysm rupture. PF4 KO mice exhibited increased neutrophil recruitment to the aneurysm wall and enhanced neutrophil activity, suggesting a negative regulatory role for PF4 in this context. We then interrogate which platelet receptors are involved in IA development. Strikingly, mice deficient for the collagen receptor, Glycoprotein VI, GPVI, were found to be protective against IA rupture, associated with increased platelet adhesion and a shift towards M2 macrophage polarization in low grade aneurysms. A striking observation across all genotypes was the predominant presence of single platelets within IAs, and intramural platelet aggregates within the vascular smooth muscle cell layer. In conclusion, our study reveals that platelets are not merely bystanders or simple mediators of thrombosis in IA, but active participants in multiple aspects of the disease process. Their roles span from hemostasis and thrombosis to inflammation, immunomodulation, and potentially vascular repair. This multifaceted involvement makes platelets both promising therapeutic targets and challenging subjects of study in IA pathology. Future research should aim to delineate these various functions in IA.