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Resténose intra-stent : évaluation de nouvelles thérapeutiques in vivo et élaboration d’un modèle in vitro hémodynamique

Abstract : In stent restenosis (ISR) is a major complication of endovascular treatment due to an excessive healing of the arterial wall. Drug eluting stents (DES) reduce the rate of ISR but expose to late stent thrombosis, related to a delayed or incomplete healing of the arterial wall, and also to hypersensitivity reactions induced by the polymer. Currently animal models are mandatory to investigate ISR as there is no reliable in vitro model. Nevertheless, these models are often far from human ISR, because of the underlying atherosclerosis process. They are also not suitable for testing DES because several experimentations and multiple samples are required. In this work, we assess the effects of two new therapeutic molecules to reduce ISR, hemin and EP224283, and we developed a new in vitro model of ISR, reproducing a hemodynamic and biological physiological environment. In vivo analysis. In stent restenosis models were stent implantation in rat abdominal aorta or in hypercholesterolemic rabbit iliac arteries. Seven or 28 days after stent implantation, the stented arteries were removed and either frozen for protein analysis or placed in fixative for morphological analysis with optical or electronical microscopy. Animals received hemin intraperitoneally or EP224283 subcutaneously every 48 hours. Control animals received saline. Histomorphological analysis at day 28 revealed that in the hemin treated group, the extent of neointima area was significantly reduced compared to the control group. A 30% decrease was observed in rats and 40% in rabbit. Endothelial coverage in electronic microscopy was similar in hemin-treated rats and rabbit when compared to their controls. The protein analysis in rats revealed that hemin limited the early inflammatory response and cellular mechanisms implicated in VSMC proliferation (ERK1/2 and p21 p27), in VSMC migration (RhoA) and reduce apoptosis. At day 28, EP224283 significantly reduced neointima growth around 20% in rats. Protein analysis revealed that EP224283 reduced vascular smooth muscle cells proliferation pathways: both ERK1/2 and Akt activated form were down-regulated in the treated rats, and p38 activated form were up-regulated. Expression of Ki67 was also reduced in both hemin and EP224283 treated group, indicating a reduced proliferation of vascular cells.Ex vivo experiments. In association with ParisTech, we developed a bioreactor for ex vivo study of ISR, providing physiologic pulsatile flow. This bioreactor will be a major tool in the research on future pro-healing DES. The bioreactor will allow: to perform numerous blood samples; study several stents at the same time; analyze flows and their effects on ISR; work directly with human arteries, collected during organ donation; and reduce the need for animal experimentation. This work demonstrated the significance of two new therapeutic molecules to prevent ISR, hemin and EP224283. Both reduced ISR without stopping the physiological healing of the arterial wall. We developed a bioreactor providing physiological and hemodynamical conditions. It will be a useful tool for the development of new DES. Our perspectives are now to create a new drug eluting stent releasing hemin or EP224283, as well as to validate our novel ex vivo hemodynamic model of ISR, in order to test our new DES in both animal models and ex vivo hemodynamic conditions.
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Blandine Maurel. Resténose intra-stent : évaluation de nouvelles thérapeutiques in vivo et élaboration d’un modèle in vitro hémodynamique. Médecine humaine et pathologie. Université du Droit et de la Santé - Lille II, 2012. Français. ⟨NNT : 2012LIL2S038⟩. ⟨tel-00856597⟩

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