Abstract
Silencing of anticoagulant protein C using RNA interference (siProc) evokes low incident but spontaneous atherothrombosis in the aortic root of apolipoprotein E–deficient (Apoe−/−) mice. The aims of the current study were (1) to analyze if plaque characteristics or circulating factors could be linked to atherothrombosis susceptibility, (2) to increase the incidence of atherothrombosis by transiently increasing blood pressure, and (3) to direct atherothrombosis to an additional predefined vascular site by applying a semi-constrictive collar around the carotid artery. siProc-driven spontaneous atherothrombosis in the aortic root of Apoe−/− mice was reproduced and occurred at an incidence of 23% (9 out of 39 mice), while the incidence of collar-induced atherothrombosis in the carotid artery was 2.6% (1 out of 39 mice). Treatment with phenylephrine, to transiently increase blood pressure, did not increase atherothrombosis in the aortic root of the Apoe−/− mice nor in the carotid arteries with collars. Plaques in the aortic root with an associated thrombus were lower in collagen and macrophage content, and mice with atherothrombosis had significantly more circulating platelets. Plasma protein C, white blood cell counts, total cholesterol, fibrinogen, serum amyloid A, and IL-6 were not different amongst siProc treated mice with or without thrombosis. Remarkably, our data revealed that thrombus formation preferably occurred on plaques in the right coronary sinus of the aortic root. In conclusion, there is a predilection of low protein C-induced spontaneous atherothrombosis in Apoe−/− mice for the right coronary sinus, a process that is associated with an increase in platelets and plaques lower in collagen and macrophage content.
Highlights
Unlike in humans, atherothrombosis does not occur spontaneously in mice, some signs of rupture or erosion and intraplaque hemorrhage have been recorded[6,7,8]
The cause for the absence of atherothrombosis is unknown, but it is likely that multiple species-specific factors such as hemodynamics, plaque composition, metabolism, and life span are involved[21]
Our group showed that transient lowering of the natural anticoagulant protein C in Apoe−/− mice resulted in spontaneous atherothrombosis at plaques formed in the sinuses of the aortic root[9]
Summary
Unlike in humans, atherothrombosis does not occur spontaneously in mice, some signs of rupture or erosion and intraplaque hemorrhage have been recorded[6,7,8]. A transient increase in blood pressure can be achieved in animal models by the administration of phenylephrine (PE), a selective α1-adrenergic receptor agonist This will increase the strain on atherosclerotic plaques and thereby stimulate the risk of plaque rupture/erosion and subsequent atherothrombosis. In the current study we applied PE treatment to increase the strain on the atherosclerotic plaques and stimulate atherothrombosis incidence in the siProc treated Apoe−/− mice. We attempted to direct atherothrombosis to the carotid artery by placing perivascular collars around the carotid artery, a procedure which induces rapid atherogenesis proximal of the collars[12] This allowed us to investigate the impact of low protein C on plaques at an additional predefined vascular site and of a different origin than the plaques in the aortic root
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