Vascular responses as therapeutic targets after SCI

描述（由申请人提供）：挫伤性脊髓损伤（SCI）引起局部内皮细胞损伤，导致血管渗漏和水肿，并引发炎症。这些过程可能导致后期组织损失和功能缺陷。血管内皮生长因子（VEGF）是由SCI诱导的，可能有助于渗漏。VEGF可能会引发有害的过程，因为我们已经表明，成年大鼠SCI后注射VEGF会增加6周时的组织损失。VEGF的药理学抑制减少中风模型中的水肿、炎症和组织损失。血管生成素1（Ang 1）诱导血管成熟，减少许多系统的渗漏，并在SCI后减少。因此，在目的1a中，将在SCI后早期施用VEGF陷阱和/或Ang 1以测试早期渗漏、水肿和炎症的减少是否减少了所选白色物质束的后期损失。在目的Ib）中，将通过用Angl加VEGF或整联蛋白激动剂保护细胞来评估内皮细胞损失对继发性损伤的贡献，因为这些可以促进体外内皮细胞存活。脊髓损伤后3-7天，损伤脊髓出现血管生成反应。新血管可以通过增加组织灌注来抵消退化，而它们的渗漏可能导致损伤。因此，在目的2a中，Angl将在血管生成阶段期间施用以促进新脉管系统的成熟和维持，可能导致更好的组织保护。新血管在第7天和第14天之间消退，因为继发性脊髓组织损失（空化）开始。这种血管生成的失败可能导致继发性损伤。在目的2b中，将通过用Angl加VEGF或Angl加整联蛋白激动剂治疗来评估维持新血管的保护作用。核心假设是通过增强稳定和成熟的血管生成，我们最终将能够减少重要的白色物质束的损失，并改善SCI后的功能性感觉和运动结果。

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.