Murine models of vascular remodeling

血管重塑的小鼠模型

基本信息

批准号：
10008792
负责人：
Manfred Boehm
金额：
$ 73.54万
依托单位：
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10008792
关键词：
Acute Affect Angioplasty Biological Assay Blood Vessels Blood flow Cell Lineage Cell Proliferation Cell Survival Cells Clinical Coculture Techniques Complex Coronary Artery Bypass Defect Development Disease Distal Dysplasia Endothelial Cells Endothelium Environment Fibroblasts Fibrosis Hindlimb Human Hyperplasia In Vitro Inflammation Inflammatory Response Intervention Investigation Ischemia Job&apos s Syndrome Knock-out Lead Ligation Medial Mediating Mesenchymal Modeling Molecular Morphology Mus Muscle Operative Surgical Procedures Outcome Pathologic Pathology Pathway interactions Patients Phase Phenotype Play Procedures Process Property Role STAT3 gene Series Signal Pathway Signal Transduction Site Smooth Muscle Myocytes Stem cells Stents Structure System Thrombosis Transforming Growth Factor beta Tube Tumor-infiltrating immune cells Vascular Diseases Vascular calcification Vascular remodeling Vein graft Veins Wound Healing angiogenesis cell type clinically relevant endothelial dysfunction experimental study femoral artery graft failure improved in vivo mouse model novel response restoration slug therapeutic target vascular smooth muscle cell migration

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一个常见过程，描述了血管壁和邻近的血管周结构内的形态变化，内皮功能障碍以及血管平滑肌细胞迁移和血管平滑的迁移和增殖是这种重塑过程，这可能导致这种重塑过程，这可能导致疾病，可能导致无刺激性杂物，杂物性杂物，杂物疾病，杂物疾病，杂物疾病，疾病血管钙化45。在干预手术（如血管成形术和血管支架）之后，还会发生血管重塑。静脉经常用于冠状动脉搭桥术中，由于血栓形成或由于病理血管重塑而导致的急性移植失败，可能在短期内失败，这是一个复杂的过程，尽管它与其他疾病有关，但尽管其临床相关。更好地了解分子信号网络和细胞反应对接受这些程序的患者具有巨大的潜力。我们已经进行了一系列研究，以确定鼠静脉移植模型中的细胞反应和局部信号通路。项目1：AD-HIES临床特征和信号通路，我们确定为在AD-HIES成纤维细胞中受影响的临床特征和信号通路，指出了血管生成缺陷是导致AD-HIES病理学的因素。因此，我们使用了体外血管生成测定的共培养来确定成纤维细胞支持血管生成的能力。我们的研究证实，AD-HIE成纤维细胞具有降低HUVEC细胞形成管形成的能力。为了研究成纤维细胞在体内支持血管生成的能力，我们使用的是后膜缺血的鼠模型，在该模型中，股动脉在特定部位的手术结扎导致动脉生成在远端缺血肌肉中脱离股骨的动脉形成。在注射广告纤维细胞的同时改善血流的恢复。这些结果表明，AD-HIS成纤维细胞在体内支持血管生成不足。项目2：移植到动脉环境中的静脉经历复杂的血管重塑。 EndMT是内皮细胞失去细胞特异性标记和形态并获得间充质细胞样表型的过程。然而，对人静脉移植物重塑过程中调节细胞表型适应的机制的作用和机制知之甚少。使用两个独立的内皮谱系跟踪系统，我们证明，在静脉移植后的35天，填充新内膜的一半细胞是内皮起源的。这些内皮衍生的细胞已经失去了内皮表型并获得了平滑肌细胞样特性，但他们未能发展出完全成熟的平滑肌细胞表型。我们检测到TGF-B-SMAD2/3-SLUG信号通路的早期激活，并确认TGF-B-SMAD2/3-SLUG信号传导途径介导的EndMT在调节静脉移植重塑中起关键作用。我们正在进一步研究BMP9/SMAD1介导的内皮细胞存活及其对急性静脉移植物通态的影响，并且由于新内膜增生的发展而导致静脉移植物重塑的长期结局，但也导致血栓形成导致早期移植物失败。我们假设激活BMP9/SMAD1途径积极调节内皮功能以使鼠静脉移植受益。