Murine models of vascular remodeling

血管重塑的小鼠模型

基本信息

项目摘要

Vascular remodeling, a common process in many vascular diseases, describes morphological changes within the vascular wall and adjacent perivascular structures Inflammation, endothelial dysfunction, and vascular smooth muscle cell migration and proliferation are the main factors triggering this remodeling process, which may lead to neointimal hyperplasia, medial dysplasia, perivascular thickening, or fibrosis and vascular calcification 45. Vascular remodeling also occurs after interventional procedures such as angioplasty and vascular stenting. Veins are frequently used in coronary artery bypass grafting, which may fail in the short term because of acute graft failure due to thrombosis or in the long term due to pathological vascular remodeling, a complex process that is poorly understood despite its clinical relevance for other diseases. A better understanding of the molecular signaling networks and cellular responses holds tremendous potential for patients undergoing these procedures. We have embarked on a series of investigations to determine cellular responses and local signaling pathways in a murine vein graft model. Project 1: AD-HIES clinical features and signaling pathways that we identified as those affected in AD-HIES fibroblasts point to angiogenesis defects as factors that contribute to AD-HIES pathologies. Therefore, we used co-culture in vitro angiogenesis assays to determine the ability of AD-HIES fibroblasts to support angiogenesis. Our studies confirmed that AD-HIES fibroblasts have decreased ability to promote tube formation by HUVEC cells. To investigate the ability of AD-HIES fibroblasts to support angiogenesis in vivo, we are using a murine model of hind-limb ischemia, in which surgical ligation of the femoral artery at specific site leads to arteriogenesis in femoral collaterals and angiogenesis in distal ischemic muscles.42 Preliminary experiments demonstrated that injecting normal fibroblasts into the calf muscle improves restoration of blood flow while injecting AD-HIES fibroblasts does not. These results indicate that AD-HIES fibroblasts are deficient in supporting angiogenesis in vivo. Project 2: Veins grafted into an arterial environment undergo complex vascular remodeling. EndMT is the process by which endothelial cells lose their cell-specific markers and morphology and acquire a mesenchymal cell-like phenotype. However, the role of EndMT and the mechanisms regulating cell phenotype adaptation during human vein graft remodeling are poorly understood. Using two independent endothelial lineage tracing systems, we demonstrated that, at 35 days after vein grafting, half the cells populating the neointima were of endothelial origin. These endothelial-derived cells had lost their endothelial phenotype and acquired smooth muscle cell-like properties, yet they failed to develop a fully mature smooth muscle cell phenotype. We detected early activation of the TGF-b-Smad2/3-Slug signaling pathway and confirmed that TGF-b-Smad2/3-Slug signaling pathway-mediated EndMT plays a pivotal role in regulating vein graft remodeling. We are further investigating BMP9/Smad1-mediated endothelial cell survival and its impact on acute vein graft patency and long-term outcome in vein graft remodeling due to the development of neointimal hyperplasia, but also in thrombosis formation leading to early graft failure. We hypothesize that activating the BMP9/Smad1 pathway positively regulates endothelial function to benefit murine vein grafting.
血管重塑是许多血管疾病中的常见过程,描述了血管壁和相邻血管周围结构内的形态学变化。炎症、内皮功能障碍和血管平滑肌细胞迁移和增殖是触发该重塑过程的主要因素,其可能导致新生内膜增生、中膜发育不良、血管周围增厚或纤维化和血管钙化45。血管重塑也发生在介入手术后,如血管成形术和血管支架植入术。静脉常用于冠状动脉旁路移植术,其可能在短期内由于血栓形成引起的急性移植物失败而失败,或在长期内由于病理性血管重塑而失败,尽管其与其他疾病的临床相关性,但对这一复杂过程知之甚少。更好地了解分子信号网络和细胞反应为接受这些手术的患者提供了巨大的潜力。我们已经开始了一系列的调查,以确定在小鼠静脉移植模型的细胞反应和局部信号通路。 项目一:我们确定的AD-HIES成纤维细胞中受影响的AD-HIES临床特征和信号通路指出血管生成缺陷是导致AD-HIES病理的因素。因此,我们使用共培养体外血管生成测定来确定AD-HIES成纤维细胞支持血管生成的能力。我们的研究证实,AD-HIES成纤维细胞促进HUVEC细胞管形成的能力降低。为了研究AD-HIES成纤维细胞支持体内血管生成的能力,我们使用后肢缺血的鼠模型,其中股动脉在特定部位的外科结扎导致股侧支动脉的动脉生成和远端缺血肌肉的血管生成。42初步实验表明,将正常成纤维细胞注射到小腿肌肉中改善了血流的恢复,而将AD-HIES成纤维细胞则没有。这些结果表明,AD-HIES成纤维细胞在支持体内血管生成方面是缺陷的。 项目2:移植到动脉环境中的静脉经历复杂的血管重塑。EndMT是内皮细胞失去其细胞特异性标志物和形态并获得间充质细胞样表型的过程。然而,EndMT在人静脉移植物重塑过程中的作用和调节细胞表型适应的机制知之甚少。 使用两个独立的内皮细胞谱系示踪系统,我们证明,在静脉移植后35天,一半的细胞填充的新生内膜内皮细胞的起源。这些内皮衍生的细胞已经失去了它们的内皮表型并获得了平滑肌细胞样的特性,但它们未能发育成完全成熟的平滑肌细胞表型。 我们检测到TGF-b-Smad 2/3-Slug信号通路的早期激活,并证实TGF-b-Smad 2/3-Slug信号通路介导的EndMT在调节静脉移植物重塑中起关键作用。我们正在进一步研究BMP 9/Smad 1介导的内皮细胞存活及其对急性静脉移植物通畅性的影响,以及由于新生内膜增生的发展而导致的静脉移植物重塑的长期结果,以及导致早期移植物失败的血栓形成。我们假设激活BMP 9/Smad 1通路积极调节内皮功能,有利于小鼠静脉移植。

项目成果

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Manfred Boehm其他文献

Manfred Boehm的其他文献

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{{ truncateString('Manfred Boehm', 18)}}的其他基金

Underlying Mechanisms in CADASIL
CADASIL 的底层机制
  • 批准号:
    10610849
  • 财政年份:
    2021
  • 资助金额:
    $ 73.54万
  • 项目类别:
Underlying Mechanisms in CADASIL
CADASIL 的底层机制
  • 批准号:
    10394276
  • 财政年份:
    2021
  • 资助金额:
    $ 73.54万
  • 项目类别:
Underlying Mechanisms in CADASIL
CADASIL 的底层机制
  • 批准号:
    10156199
  • 财政年份:
    2021
  • 资助金额:
    $ 73.54万
  • 项目类别:
Underlying Mechanisms of Vascular Disease
血管疾病的潜在机制
  • 批准号:
    9288213
  • 财政年份:
    2016
  • 资助金额:
    $ 73.54万
  • 项目类别:
Murine models of vascular remodeling
血管重塑的小鼠模型
  • 批准号:
    8746649
  • 财政年份:
  • 资助金额:
    $ 73.54万
  • 项目类别:
iPS-technology and patient specific disease models
iPS 技术和患者特定疾病模型
  • 批准号:
    8746650
  • 财政年份:
  • 资助金额:
    $ 73.54万
  • 项目类别:
iPS-technology and patient specific disease models
iPS 技术和患者特定疾病模型
  • 批准号:
    8939854
  • 财政年份:
  • 资助金额:
    $ 73.54万
  • 项目类别:
iPS-technology and patient specific disease models
iPS 技术和患者特定疾病模型
  • 批准号:
    9157402
  • 财政年份:
  • 资助金额:
    $ 73.54万
  • 项目类别:
Vascular remodeling in patients with rare genetic disorders
罕见遗传性疾病患者的血管重塑
  • 批准号:
    10929131
  • 财政年份:
  • 资助金额:
    $ 73.54万
  • 项目类别:
Murine models of vascular remodeling
血管重塑的小鼠模型
  • 批准号:
    8158040
  • 财政年份:
  • 资助金额:
    $ 73.54万
  • 项目类别:

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