Axitinib attenuates intraplaque angiogenesis, haemorrhages and plaque destabilization in mice

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Axitinib attenuates intraplaque angiogenesis, haemorrhages and plaque destabilization in mice


Abstract
Aim
An increased density of intraplaque (IP) microvessels in ruptured versus nonruptured human plaques suggests that IP neovascularization has a major causative effect on plaque development and instability. Possibly, vascular endothelial growth factor (VEGF) or other angiogenic factors mediate IP microvessel growth and plaque destabilization. Because apolipoprotein deficient mice with a heterozygous mutation (C1039G +/−) in the fibrillin-1 gene (ApoE−/− Fbn1C1039G +/−) manifest substantial IP neovascularization, they represent a unique tool to further investigate angiogenesis and its role in atherosclerosis. Here, we examined whether administration of axitinib (inhibitor of VEGF receptor-1,-2 and -3) inhibits IP neovascularization and stabilizes atherosclerotic plaques.

Methods
ApoE−/− Fbn1C1039G +/− mice were fed a western diet (WD) for 20 weeks. After 14 weeks WD, mice received axitinib (35 μg/g) or solvent i.p. 4 ×/week for 6 weeks. Cardiac function was monitored to evaluate the effect of axitinib on atherosclerosis-driven complications such as myocardial infarction.

Results
Axitinib significantly reduced IP neovascularization, with subsequent less prevalence of IP haemorrhages. The smooth muscle cell content doubled, whereas the amount of macrophages decreased. Overall cardiac function was improved in axitinib-treated animals. Moreover, the number of animals with myocardial infarction was decreased by 40%. Coronary plaque formation was observed in almost all control animals whereas treated animals showed a 30% reduction in the occurrence of coronary plaques.

Conclusions
Inhibition of VEGF receptor signalling by axitinib attenuates intraplaque angiogenesis and plaque destabilization in mice.


https://www.sciencedirect.com/science/a ... 9117301519