Hypoxia and hypoxia-inducible factors promote the development of neointimal hyperplasia in arteriovenous fistula.
Hypoxia and hypoxia-inducible factors promote the development of neointimal hyperplasia in arteriovenous fistula.
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DOI：
10.1113/jp281218
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Mazure NM
中科院分区：
文献类型：
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作者：
Sadaghianloo N;Contenti J;Declemy S;Ambrosetti D;Zdralevic M;Tannour-Louet M;Fabbri L;Pagès G;Bost F;Hassen-Khodja R;Pouysségur J;Jean-Baptiste E;Dardik A;Mazure NM
由于动静脉瘘(AVF)手术过程中静脉壁、周围组织和血液中氧浓度的变化，我们推测缺氧可能是由于新生内膜增生导致AVF失败的原因。我们推测，药物对缺氧诱导因子(HIF)的调节可以促进AVF的成熟。体外实验观察了静脉壁三层成纤维细胞、血管内皮细胞和血管内皮细胞的增殖、细胞死亡、代谢、ROS的产生和迁移，以及经去铁胺、伊维莫司、二甲双胍、N-乙酰-L半胱氨酸和拓扑异构酶I处理后的细胞增殖、细胞死亡、代谢、ROS的产生和迁移。在小鼠的动静脉瘘模型中，将被认为最有可能改善内膜增生的化合物局部应用于血管。我们发现，在体外，NHF和HUVSMC可以根据氧浓度调整它们的新陈代谢，从而适应它们的生长，而HUVEC似乎不太灵活。SiHIF1/2、α、DFO、EVE、Met、NAc和Topo可根据细胞类型和氧浓度调节细胞的代谢和增殖。在体内，siHIF1/2α、EVE和TOPO在治疗后7天减少新生内膜增生32-50%。在血管壁内，缺氧和HIF-1/2介导了AVF的早期失效。局部给予针对HIF-1/2的药物可抑制动静脉瘘小鼠模型的新生内膜增生。这样的化合物可以在动静脉动静脉瘘形成的外科手术过程中输送，以防止早期动静脉动静脉瘘失败。
Since oxygen concentration changes in the venous wall, surrounding tissue and the blood during surgical creation of arteriovenous fistula (AVF), we hypothesized that hypoxia could contribute to AVF failure due to neointimal hyperplasia. We postulated that modulation of the hypoxia-inducible factors (HIF) with pharmacological compounds could promote AVF maturation. Fibroblasts (NHF), smooth muscle cells (HUVSMC) and endothelial cells (HUVEC), representing the three layers of the venous wall, were tested in vitro for proliferation, cell death, metabolism, ROS production and migration after silencing of HIF1/2-α or after treatment with deferioxamine (DFO), everolimus (Eve), metformin (Met), N-acetyl-L-cysteine (NAC) and topoisomerase I (TOPO) that modulate HIF-α stability or activity. Compounds that were considered most likely to modify intimal hyperplasia were applied locally to the vessels in a mouse model of aortocaval fistula. We showed, in vitro, that NHF and HUVSMC can adapt their metabolism and thus their growth depending on oxygen concentration, whereas HUVEC seem to be less flexible. siHIF1/2α, DFO, Eve, Met, NAC and TOPO can modulate metabolism and proliferation depending on the cell type and the oxygen concentration. In vivo, siHIF1/2α, Eve and TOPO decreased neointimal hyperplasia by 32–50% seven days after the treatment. Within vascular wall, hypoxia and HIF-1/2 mediate early failure of AVF. Local delivery of drugs targeting HIF-1/2 could inhibit neointimal hyperplasia in a mouse model of AVF. Such compounds may be delivered during the surgical procedure for AVF creation to prevent early AVF failure.