Vascular responses as therapeutic targets after SCI

描述（由申请人提供）：挫伤性脊髓损伤（挫伤spinal cord injury， SCI）引起局部内皮细胞损伤，导致血管渗漏和水肿，引发炎症。这些过程可能导致后来的组织损失和功能缺陷。血管内皮生长因子（Vascular endothelial growth factor， VEGF）是脊髓损伤诱导的，可能是导致血管渗漏的原因之一。VEGF可能会启动有害的过程，正如我们所显示的，成年大鼠脊髓损伤后注射VEGF会增加六周后的组织损失。药物抑制VEGF可减少脑卒中模型的水肿、炎症和组织损失。血管生成素1 （Ang1）在许多系统中诱导血管成熟并减少渗漏，在脊髓损伤后减少。因此，在aim la中，将在脊髓损伤后早期给予VEGF诱捕器和/或Ang1，以测试早期渗漏、水肿和炎症的减少是否会减少后来选定的白质束的损失。在aim lb中，内皮细胞损失对继发性损伤的贡献将通过使用Ang1 + VEGF或整合素激动剂来保护细胞来评估，因为它们可以促进内皮细胞在体外的存活。脊髓损伤后3-7天，受损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变性，而它们的渗漏可能会造成损伤。因此，在aim 2a中，Ang1将在血管生成阶段给予，以促进新血管的成熟和维持，可能导致更好的组织保护。随着继发性脊髓组织丢失（空化）开始，新生血管在第7天至第14天之间退化。这种血管生成功能衰竭可能导致继发性损伤。在aim 2b中，将通过使用Ang1 + VEGF或Ang1 +整合素激动剂来评估维持新生血管的保护作用。核心假设是，通过增强稳定和成熟的血管生成，我们最终能够减少重要白质束的损失，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.