Vascular responses as therapeutic targets after SCI

描述(申请人提供)：脊髓损伤(SCI)导致局部内皮细胞损伤，导致血管渗漏和水肿，并引发炎症。这些过程可能会导致以后的组织丢失和功能缺陷。血管内皮生长因子(VEGF)是由脊髓损伤诱导的，可能参与了脊髓损伤后的渗漏。血管内皮生长因子可能会启动有害的过程，因为我们已经证明，成年大鼠脊髓损伤后注射血管内皮生长因子会增加六周时的组织丢失。血管内皮生长因子的药理抑制可减少中风模型中的水肿、炎症和组织丢失。血管生成素1(Ang1)在许多系统中诱导血管成熟，减少渗漏，在脊髓损伤后减少。因此，在AIM 1a中，将在脊髓损伤后早期给予血管内皮生长因子陷阱和/或血管紧张素转换酶1，以测试早期渗漏、水肿和炎症的减少是否减少了后来选定的白质束的丢失。目的：通过使用Ang1加血管内皮生长因子或整合素激动剂保护内皮细胞来评估内皮细胞丢失在二次损伤中的作用，因为这些都可以促进内皮细胞在体外的存活。脊髓损伤后3-7天，损伤脊髓出现新生血管反应。新的血管可能会通过增加组织灌注量来抵消退化，而它们的泄漏可能会造成损害。因此，在Aim 2a中，Ang1将在血管生成阶段使用，以促进新血管的成熟和维持，可能会产生更好的组织保护。随着继发性脊髓组织丢失(空化)的开始，新血管在第7天到第14天之间消退。这种血管生成失败可能是继发性损伤的原因之一。在目标2b中，将通过使用Ang1加血管内皮生长因子或Ang1加整合素激动剂来评估维持新血管的保护作用。中心假设是，通过促进稳定和成熟的血管生成，我们最终将能够减少重要白质束的丢失，并改善脊髓损伤后的功能感觉和运动结果。

DESCRIPTION (provided by applicant): Contusive spinal cord injury (SCI) causes local endothelial cell damage, resulting in vascular leakage and edema and the initiation of inflammation. These processes may lead to later tissue loss and functional deficits. Vascular endothelial growth factor (VEGF) is induced by SCI and may contribute to the leakage. VEGF may initiate detrimental processes, as we have shown that VEGF injections after SCI in adult rats increases tissue loss seen at six weeks. Pharmacological inhibition of VEGF reduces edema, inflammation and tissue loss in stroke models. Angiopoietin 1 (Ang1) induces vessel maturation and reduces leakage in many systems and is reduced after SCI. Therefore, in aim la, a VEGF trap and/or Ang1 will be administered early after SCI to test whether reduction of early leakage, edema and inflammation reduces later loss of selected white matter tracts. In aim lb) the contribution of endothelial cell loss to secondary damage will be evaluated by protecting the cells with Ang1 plus VEGF or integrin agonist, as these can promote endothelial cell survival in vitro. From 3-7 days after SCI, an angiogenic response occurs in the injured cord. New vessels may counteract degeneration by increased tissue perfusion, while their leakage may cause damage. Thus, in aim 2a, Ang1, will be administered during the angiogenic phase to promote maturation and maintenance of the new vasculature, possibly resulting in better tissue protection. The new blood vessels regress between day 7 and 14 as secondary spinal tissue loss (cavitation) begins. This angiogenic failure may contribute to the secondary damage. In aim 2b, the protective effects of maintaining the new blood vessels will be assessed by treating with Ang1 plus VEGF or Ang1 plus integrin agonist. The central hypothesis is that by enhancing stable and mature angiogenesis we will ultimately be able to reduce loss of important white matter tracts and improve functional sensory and motor outcome after SCI.