Mechanical Stretch and Vein Graft Intimal Hyperplasia

描述（由申请人提供）：静脉旁路移植物通常用于置换功能障碍的动脉。然而，由于机械拉伸和涡流血流诱导的内膜增生，静脉移植物失败。机械拉伸已显示诱导广泛的血管细胞死亡，随后不久过度的血管细胞增殖和内膜增生。我们的长期目标是确定早期机械牵张依赖性血管细胞死亡与静脉移植物中晚期血管细胞增殖和内膜增生的关系。阐明血管细胞死亡和增殖之间的关系可能会提供新的方法来预防或减少内膜增生，这是一个关键的事件，在失败的面纱移植。由于涡旋血流有助于静脉移植物损伤和重塑，并可能掩盖机械拉伸的作用，我们已经开发了一种全新的实验静脉移植模型，其中涡旋血流的发展是通过密切匹配移植物和宿主动脉直径来防止的。因此，我们的模型独特地允许我们在生理相关模型中研究机械拉伸的作用，而不受涡旋血流的混杂影响。我们计划在以下阶段实现我们的目标：1）阐明在实验性静脉移植物重塑的早期阶段介导牵张依赖性血管细胞死亡的信号分子; 2）阐明介导牵张依赖性血管细胞增殖和内膜增生的信号分子和生长因子; 3）确定血管细胞死亡的程度是否影响生长因子的产生以及随后的血管细胞增殖和内膜增生的程度。具体目的I：研究p38 MAPK和JNK-SAPK在介导实验性静脉移植物牵张依赖性细胞死亡中的作用。具体目标二：研究血小板衍生生长因子（PDGF）-BB和相关信号分子在介导随后的血管细胞增殖中的作用。

DESCRIPTION (provided by applicant): Vein bypass grafts are commonly used to replace malfunctioned arteries. However, vein grafts fail due to intimal hyperplasia induced by mechanical stretch and vortex blood flow. Mechanical stretch has been shown to induce extensive vascular cell death followed shortly thereafter by excessive vascular cell proliferation and intimal hyperplasia. Our long term goal is to determine a relationship of early stage mechanical stretch dependent vascular cell death to late stage vascular cell proliferation and intimal hyperplasia in a vein graft. Elucidation of a relationship between vascular cell death and proliferation may provide novel methods to prevent or reduce intimal hyperplasia, which is a critical event in the failure of veil grafts. Because vortex blood flow contributes to vein graft injury and remodeling and can obscure the role of mechanical stretch, we have developed an entirely novel experimental vein graft model where the development of vortex blood flow is prevented by closely matching graft and host artery diameters. Therefore, our model uniquely allows us to investigate the role of mechanical stretch in a physiologically relevant model without the confounding influence of vortex blood flow. We plan to approach our goal in the following stages: 1) clarify the signaling molecules that mediate stretch dependent vascular cell death during early stages of experimental vein graft remodeling; 2) clarify the signaling molecules and growth factors that mediate stretch-dependent vascular cell proliferation and intimal hyperplasia; 3) determine whether the degree of vascular cell death influences the production of growth factors and the degree of subsequent vascular cell proliferation and intimal hyperplasia. Specific Aim I: Investigate the role of p38 MAPK and JNK-SAPK in mediating stretch-dependent cell death in experimental vein grafts. Specific Aim II: Investigate the role of platelet-derived growth factor (PDGF)-BB and related signaling molecules in mediating subsequent vascular cell proliferation.