Mechanical Stretch and Vein Graft Intimal Hyperplasia

描述(申请人提供)：静脉搭桥术通常用于替代功能不全的动脉。然而，由于机械拉伸和涡旋血流导致的内膜增生，静脉移植失败。机械拉伸可导致广泛的血管细胞死亡，随后不久血管细胞过度增殖和内膜增生。我们的长期目标是确定移植静脉中早期机械拉伸依赖的血管细胞死亡与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为预防或减少内膜增生提供新的方法，而内膜增生是面纱移植物失败的关键事件。由于旋涡血流导致静脉移植物损伤和重塑，并可能掩盖机械拉伸的作用，我们开发了一种全新的实验性静脉移植物模型，通过紧密匹配移植物和宿主动脉的直径来防止旋涡血流的发展。因此，我们的模型独一无二地允许我们在一个生理相关的模型中研究机械拉伸的作用，而不会受到涡旋血流的混杂影响。我们计划在以下几个阶段实现我们的目标：1)阐明在实验性静脉移植重建的早期阶段介导拉伸依赖性血管细胞死亡的信号分子；2)阐明介导拉伸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血管细胞增殖和内膜增生的程度。目的1：探讨p38MAPK和JNK-SAPK在实验性移植静脉牵张依赖性细胞死亡中的作用。特定目的II：探讨血小板衍生生长因子(PDGF)-BB及其相关信号分子在介导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.