BIODYNAMIC FACTORS IN VEIN GRAFT HYPERPLASIA

移植静脉增生的生物动力学因素

• 批准号: 2229413
• 负责人: WILLIAM M ABBOTT
• 金额: $ 29.72万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-04-01 至 1999-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2229413
• 关键词: biomechanics; collagen; growth factor; hemodynamics; hemostasis; human tissue; hyperplasia; mechanical stress; oxygen tension; phantom model; plasminogen activator; platelet aggregation; tissue /cell culture; urokinase; vascular smooth muscle

All forms of intervention in the arterial circulation may result in intimal hyperplasia (IH)of the involved vessels. These include endarterectomy, balloon dilatation (so-called angioplasty), and bypass grafting procedures, where IH is found to develop in both the graft and at the anastomoses. IH occurs focally or globally, in a significant number of saphenous vein grafts utilized for coronary artery or peripheral artery bypass grafts, where it reaches pathological proportions which result in hemodynamically significant stenosis and occlusion. Surgeons and cardiologists recognize it as an extremely serious problem and there are many who would categorically argue that IH is the number one unsolved problem in the field of vascular surgery. Although IH is a common problem, multiple factors have been associated with its cause and there are no known reliable measures to prevent it or to treat it when it does occur. The working hypothesis of this grant is that with the conversion of a vein (graft) into an arterial conduit, several abrupt changes in wall motion, fluid shear, and oxygen tension occur which alone, or in combination, may functionally alter vascular wall cells and thereby "trigger" the onset of hyperplasia. In this proposal, we will evaluate the functional consequences of these biomechanical and hemodynamic changes, both independently and together, on adult human venous endothelial (EC) and smooth muscle (SMC) cells that have been cultured in a compliant tubular system of our design (Vascular Simulating Device or VSD). In this apparatus, wall motion and fluid shear can be varied independently or in concert. Using the VSD, we will subject EC and SMC to specific levels of mechanical and/or hemodynamic forces which, in vivo, have been correlated with the most intense hyperplastic responses. We will then evaluate the influence of these forces on those cellular functions involved in the development of IH. These include proliferative activity and growth factor production, matrix deposition, and altered thrombotic response. Ultimately we wish to identify the direct cellular targets (eg, transcription factors and promoter elements) that are responsive to specific physical perturbations. Finally, the effects of altered ambient oxygen tension upon IH will be studied. In these experiments, those physical perturbations identified as most critical will be repeated in the VSD under conditions in which a low O2 tension, innate to the venous circulation will be abruptly changed to that of the arterial circulation. The combined experimental results will enable us to identify those biomechanical parameters which induce vein graft hyperplasia. With these factors clearly in focus, we will ultimately be able to develop potential strategies directed against IH.

所有形式的动脉循环干预都可能导致 相关血管的内膜增生（IH）。这些包括 动脉内膜切除术、球囊扩张术（所谓的血管成形术）和搭桥术 移植手术中，发现移植物和移植处均出现 IH 吻合术。 IH 发生在局部或全身，在相当多的病例中 用于冠状动脉或外周动脉的大隐静脉移植物 旁路移植，达到病理程度，导致 血流动力学显着的狭窄和闭塞。外科医生和 心脏病专家认为这是一个极其严重的问题 许多人断然认为 IH 是第一个未解决的问题 血管外科领域的问题。尽管 IH 是一个常见问题， 其原因与多种因素有关，目前尚无定论 已知可靠的措施来预防或在发生时进行治疗。 这项资助的工作假设是，通过静脉的转换 （移植物）进入动脉导管，室壁运动发生几次突然变化， 流体剪切力和氧张力的发生单独或组合可能 功能上改变血管壁细胞，从而“触发” 增生。在本提案中，我们将评估功能 这些生物力学和血流动力学变化的后果 独立和共同对成人静脉内皮细胞（EC）和 在顺应性肾小管中培养的平滑肌 (SMC) 细胞 我们设计的系统（血管模拟装置或 VSD）。在这个 装置、壁运动和流体剪切可以独立变化或同时变化 音乐会。使用 VSD，我们将使 EC 和 SMC 达到特定级别 体内相关的机械力和/或血流动力 具有最强烈的增生反应。然后我们将评估 这些力对参与细胞功能的影响 IH的发展。这些包括增殖活性和生长因子 产生、基质沉积和血栓反应改变。 最终我们希望确定直接的细胞目标（例如， 转录因子和启动子元件）对 特定的物理扰动。最后，改变环境的影响 将研究 IH 时的氧张力。在这些实验中，那些 被确定为最严重的物理扰动将在 VSD 在静脉固有的低氧张力条件下发生 循环将突然改变为动脉循环。 综合实验结果将使我们能够识别那些 诱导静脉移植物增生的生物力学参数。 有了这些 明确重点因素，我们最终将能够开发潜力 针对 IH 的策略。