Differential Proteoglycan Expression in Atherosclerosis Alters Platelet Adhesion and Activation.

Proteoglycans are differentially expressed in different atherosclerotic plaque phenotypes, with biglycan and decorin characteristic of ruptured plaques and versican and hyaluronan more prominent in eroded plaques. Following plaque disruption, the exposure of extracellular matrix (ECM) proteins triggers platelet adhesion and thrombus formation. In this study, the impact of differential plaque composition on platelet function and thrombus formation was investigated. Platelet adhesion, activation and thrombus formation under different shear stress conditions were assessed in response to individual proteoglycans and composites representing different plaque phenotypes. The results demonstrated that all the proteoglycans tested mediated platelet adhesion but not platelet activation, and the extent of adhesion observed was significantly lower than that observed with type I and type III collagens. Thrombus formation upon the rupture and erosion ECM composites was significantly reduced (p < 0.05) compared to relevant collagen alone, indicating that proteoglycans negatively regulate platelet collagen responses. This was supported by results demonstrating that the addition of soluble biglycan or decorin to whole blood markedly reduced thrombus formation on type I collagen (p < 0.05). Interestingly, thrombus formation upon the erosion composite displayed aspirin sensitivity, whereas the rupture composite was intensive to aspirin, having implications for current antiplatelet therapy regimes. In conclusion, differential platelet responses and antiplatelet efficacy are observed on ECM composites phenotypic of plaque rupture and erosion. Proteoglycans inhibit thrombus formation and may offer a novel plaque-specific approach to limit arterial thrombosis.

Modelling arterial thrombus formation in vitro.

PURPOSE OF REVIEW: Models of arterial thrombus formation represent a vital experimental tool to investigate platelet function and test novel antithrombotic drugs. This review highlights some of the recent advances in modelling thrombus formation in vitro and suggests potential future directions. RECENT FINDINGS: Microfluidic devices and the availability of commercial chips in addition to enhanced accessibility of 3D printing has facilitated a rapid surge in the development of novel in-vitro thrombosis models. These include progression towards more sophisticated, 'vessel on a chip' models which incorporate vascular endothelial cells and smooth muscle cells. Other approaches include the addition of branches to the traditional single channel to yield an occlusive model; and developments in the adhesive coating of microfluidic chambers to better mimic the thrombogenic surface exposed following plaque rupture. Future developments in the drive to create more biologically relevant chambers could see a move towards the use of human placental vessels, perfused ex-vivo. However, further work is required to determine the feasibility and validity of this approach. SUMMARY: Recent advances in thrombus formation models have significantly improved the pathophysiological relevance of in-vitro flow chambers to better reflect the in-vivo environment and provide a more translational platform to test novel antithrombotics.

The Contribution of Vascular Proteoglycans to Atherothrombosis: Clinical Implications.

The vascular extracellular matrix (ECM) produced by endothelial and smooth muscle cells is composed of collagens and glycoproteins and plays an integral role in regulating the structure and function of the vascular wall. Alteration in the expression of these proteins is associated with endothelial dysfunction and has been implicated in the development and progression of atherosclerosis. The ECM composition of atherosclerotic plaques varies depending on plaque phenotype and vulnerability, with distinct differences observed between ruptured and erodes plaques. Moreover, the thrombi on the exposed ECM are diverse in structure and composition, suggesting that the best antithrombotic approach may differ depending on plaque phenotype. This review provides a comprehensive overview of the role of proteoglycans in atherogenesis and thrombosis. It discusses the differential expression of the proteoglycans in different plaque phenotypes and the potential impact on platelet function and thrombosis. Finally, the review highlights the importance of this concept in developing a targeted approach to antithrombotic treatments to improve clinical outcomes in cardiovascular disease.