Coagulation, the process of blood clot formation, has two stages: primary and secondary hemostasis. In primary hemostasis, platelets form a plug, while in secondary hemostasis, coagulation factors... Show moreCoagulation, the process of blood clot formation, has two stages: primary and secondary hemostasis. In primary hemostasis, platelets form a plug, while in secondary hemostasis, coagulation factors create a stable fibrin clot. Von Willebrand factor (VWF) protein plays an essential role in the primary hemostasis, initiating platelet adhesion. Abnormal VWF levels can cause hemostatic disorders, with low levels leading to von Willebrand disease (VWD), the most common inherited bleeding disorder, and high levels raising the risk of (arterial) thrombosis. Treatments for thrombosis traditionally inhibit platelet aggregation, but disadvantages include resistance or bleeding complications. While there are inhibitors of VWF function to reduce thrombosis risk, in this thesis we explore the feasibility of inhibiting the production of VWF. Here, we performed allele-selective silencing of murine endothelial Vwf in mice using siRNAs. We demonstrated that a 50% VWF reduction lowers thrombus formation without increasing bleeding times. Murine-specific siRNAs encapsulated in lipid nanoparticles showed successful delivery to the endothelium, both under normal and diseased conditions. All in all, our suggest that siRNA-mediated Vwf-silencing could offer a new therapeutic approach for both VWD and thrombotic disorders. These findings support further exploration of allele-selective VWF silencing for clinical applications in hemostatic management. Show less
Cardiovascular disease is the leading cause of death worldwide. The primary underlying pathology of cardiovascular disease is atherosclerosis. Atherosclerosis is a chronic, multifactorial disease... Show moreCardiovascular disease is the leading cause of death worldwide. The primary underlying pathology of cardiovascular disease is atherosclerosis. Atherosclerosis is a chronic, multifactorial disease in which lipid accumulates in the arterial wall, leading to a local inflammatory reaction and atherosclerotic plaque formation. Atherosclerotic disease develops largely asymptomatic over a lifetime. However, plaque rupture or erosion can cause the formation of a superimposed thrombus, blocking the flow of blood, and cause acute cardiovascular events such as myocardial infarction or ischemic stroke. Defects in cholesterol metabolism and hypercholesterolemia, which are major risk factors for atherosclerosis, have been shown to affect hematopoiesis, immune cell production and platelet counts and reactivity. Therefore, bone marrow cholesterol handling is an interesting target in the battle against cardiovascular disease, and acute cardiovascular events in particular. This thesis describes novel interactions between cholesterol metabolism and the production of immune cells and platelets, and its effects on atherosclerosis and atherothrombosis development. Show less
Ouweneel, A.B.; Verwilligen, R.A.F.; Eck, M. van 2019
Atherothrombotic events such as myocardial infarction and ischemic stroke are a major cause of morbidity and mortality worldwide. Understanding the molecular and cellular mechanisms of... Show moreAtherothrombotic events such as myocardial infarction and ischemic stroke are a major cause of morbidity and mortality worldwide. Understanding the molecular and cellular mechanisms of atherosclerotic plaque destabilization or erosion, and developing new therapeutics to prevent acute cardiovascular events is important for vascular biology research and clinical cardiovascular medicine. However, basic research on plaque destabilization, rupture and erosion is hampered by the lack of appropriate animal models of atherothrombosis. Unprovoked atherothrombosis is very scarce in commonly used mouse models for atherosclerosis, the low-density lipoprotein receptor knockout and apolipoprotein E knockout mice. Therefore, specific interventions are required to induce atherothrombosis in these models. Two strategies can be employed to induce atherothrombosis: 1) plaque destabilization and 2) induction of blood hypercoagulability. Although the individual strategies yield atherothrombosis at low incidence, it appears that the combination of both plaque destabilization and an increase in blood coagulability is the most promising strategy to induce atherothrombosis on a larger scale. In this review, we summarize the recent developments on mouse models for the investigation of atherothrombosis. Show less
Ouweneel, A.B.; Heestermans, M.; Verwilligen, R.A.F.; Gijbels, M.J.J.; Reitsma, P.H.; Eck, M. van; Vlijmen, B.J.M. van 2017
Murine atherosclerosis models do not spontaneously develop atherothrombotic complications. We investigated whether disruption of natural anticoagulation allows preexisting atherosclerotic plaques... Show moreMurine atherosclerosis models do not spontaneously develop atherothrombotic complications. We investigated whether disruption of natural anticoagulation allows preexisting atherosclerotic plaques to progress toward an atherothrombotic phenotype. Mice featured clots in the left atrium of the heart. Our findings indicate that small interfering RNA-mediated silencing of protein C in apolipoprotein E-deficient mice creates a condition that allows the occurrence of spontaneous atherothrombosis, albeit at a low incidence. Lowering natural anticoagulation in atherosclerosis models may help to discover factors that increase atherothrombotic complications. Show less
Atherothrombosis is a complication of atherosclerosis that causes acute cardiovascular events such as myocardial infarction and stroke. Circulating lipid levels are highly correlated with... Show moreAtherothrombosis is a complication of atherosclerosis that causes acute cardiovascular events such as myocardial infarction and stroke. Circulating lipid levels are highly correlated with atherosclerotic plaque development. In addition, experimental evidence suggests that lipids also directly influence thrombosis and influence the risk and the outcome of acute cardiovascular events. Plasma lipoproteins influence three aspects important to atherothrombosis: endothelial function, platelet aggregation (primary coagulation) and secondary coagulation. Overall, VLDL, LDL and oxLDL promote thrombus formation, whereas HDL shows antithrombotic actions. In this review we will address the current knowledge about modulation of atherothrombosis by lipoproteins, summarizing findings from in vitro and in vivo animal studies, as well as from observational and interventional studies in humans. We will conclude with future perspectives for lipid modulation in the prevention of atherothrombosis. Show less
