RESUMO
BACKGROUND: Platelets are believed to play an important role in atherogenesis and the vessel response to vascular injury. The P2Y(12) receptor (P2Y(12)) plays a central role in amplifying platelet aggregation, dense granule and alpha-granule secretion, P-selectin expression, microparticle formation, and procoagulant membrane changes, regardless of the activating stimulus. We hypothesized that P2Y(12) deficiency might reduce the vessel wall response to vascular injury as well as thrombosis in murine vascular injury models. METHODS AND RESULTS: P2Y(12)-deficient (-/-) mice and littermate controls (+/+) were bred on a C57 BL/6 background. In vivo murine models of arterial injury were employed alone and in combination with bone marrow transplantation to investigate the role of P2Y(12) in the vessel wall response to arterial injury and thrombosis. At 21 days after ferric chloride injury, neointima formation in P2Y(12)(-/-) arteries was significantly less than that observed in control strain arteries (P<0.025). In agreement with this, the intima-media ratio was significantly greater in femoral wire-injured arteries from P2Y(12)(+/+) compared with P2Y(12)(-/-) animals (P<0.05). Bone marrow transplantation was used to examine the importance of vessel wall P2Y(12) versus platelet P2Y(12). Analysis of arterial sections from chimeric animals at 21 days after injury revealed a smaller intima-media ratio in -/- to +/+ animals than in the positive (+/+ to +/+) control group (P<0.01). CONCLUSIONS: These data demonstrate a role for platelet P2Y(12) in the vessel wall response to arterial injury and thrombosis. This illustrates the manner in which platelets may contribute to atherogenesis and restenosis.
Assuntos
Plaquetas/fisiologia , Artéria Femoral/lesões , Receptores Purinérgicos P2/genética , Receptores Purinérgicos P2/metabolismo , Trombose/fisiopatologia , Animais , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Plaquetas/patologia , Transplante de Medula Óssea , Cloretos , Modelos Animais de Doenças , Feminino , Artéria Femoral/patologia , Artéria Femoral/fisiopatologia , Compostos Férricos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Músculo Liso Vascular/patologia , Músculo Liso Vascular/fisiopatologia , Noxas/toxicidade , Selectina-P/metabolismo , Agregação Plaquetária/fisiologia , Receptores Purinérgicos P2Y12 , Trombose/patologia , Túnica Íntima/lesões , Túnica Íntima/patologia , Túnica Íntima/fisiopatologiaRESUMO
The inherent complexity of biomedical systems is well recognized; they are multiscale, multiscience systems, bridging a wide range of temporal and spatial scales. While the importance of multiscale modelling in this context is increasingly recognized, there is little underpinning literature on the methodology and generic description of the process. The COAST (complex autonoma simulation technique) project aims to address this by developing a multiscale, multiscience framework, coined complex autonoma (CxA), based on a hierarchical aggregation of coupled cellular automata (CA) and agent-based models (ABMs). The key tenet of COAST is that a multiscale system can be decomposed into N single-scale CA or ABMs that mutually interact across the scales. Decomposition is facilitated by building a scale separation map on which each single-scale system is represented according to its spatial and temporal characteristics. Processes having well-separated scales are thus easily identified as the components of the multiscale model. This paper focuses on methodology, introduces the concept of the CxA and demonstrates its use in the generation of a multiscale model of the physical and biological processes implicated in a challenging and clinically relevant problem, namely coronary artery in-stent restenosis.
