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Project

Stabilization of atherosclerotic plaques via inhibition of intraplaque neovascularization.

Atherosclerosis is an inflammatory disorder of the arterial wall leading to myocardial infarction, stroke and peripheral arterial disease. Recently, we published that elastin fragmentation, due to a mutation (C1039G+/-) in the fibrillin-1 (Fbn1) gene, promotes atherogenesis and a highly unstable plaque phenotype in apolipoprotein E deficient (ApoE-/-) mice on a Western-type diet. Interestingly, ApoE-/-Fbn1C1039G+/- mice reveal substantial intraplaque (IP) neovascularization, which is a typical feature of advanced human atherosclerotic plaques, but rarely observed in animal models. Because clinical evidence links IP angiogenesis with progressive and unstable vascular disease, we will investigate whether inhibition of IP neovascularization has a beneficial effect on atherogenesis and plaque stability. Hitherto, blocking VEGF was the primary strategy to reduce neovascularization. Unfortunately, limited efficacy and adverse effects have downsized its success, even when multiple blockers were used simultaneously. Therefore, a fundamentally different approach was needed to re-boost the image of anti-angiogenic therapy. Given that endothelial cells (ECs) rely on glycolysis for up to 85% of their energy demand, targeting the glycolytic pathway represents an attractive new strategy to inhibit neovascularization. Studies in the oncology field already showed that transient and partial inhibition of glycolysis in proliferating ECs inhibits pathological angiogenesis without interfering in the metabolism of healthy cells. Therefore, this project has the following three objectives, each associated to a dedicated work package:(1) Inhibition of glycolytic flux by deletion of a key regulating enzyme in glycolysis (PFKFB3) specifically in ECs. We will examine the effects of PFKFB3 deletion in ECs on atherogenesis and plaque stability using ApoE-/- Fbn1C1039G+/- mice.(2) Pharmacological inhibition of IP angiogenesis in ApoE-/- Fbn1C1039G+/- mice using PFKFB3 inhibitor 3PO or alternative compounds that specifically bind PFKFB3.(3) Development of an imaging tool to evaluate inhibition of IP neovascularization using advanced microscopy techniques.For each work package, several tasks have already been completed, highlighting (i) the feasibility of this DOCPRO1 project and ii) the need for the additional and final year to bring this PhD project to a successful end.
Date:15 Jul 2018 →  14 Jul 2019
Keywords:ATHEROSCLEROSIS, ENDOTHELIAL CELLS, NEOVASCULARISATION
Disciplines:Cardiac and vascular medicine, Biomarker discovery and evaluation, Drug discovery and development, Medicinal products, Pharmaceutics, Pharmacognosy and phytochemistry, Pharmacology, Pharmacotherapy, Toxicology and toxinology, Other pharmaceutical sciences