Aging dampens compensatory angiogenesis via downregulation of VEGF signaling in subcortical ischemic vascular dementia

衰老通过下调皮层下缺血性血管性痴呆中 VEGF 信号传导抑制代偿性血管生成

• 批准号: 9916420
• 负责人: Ken Arai
• 金额: $ 45.32万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916420
• 关键词: Adult; Affect; Age; Aging; Animal Model; Blood - brain barrier anatomy; Blood Vessels; Blood flow; Brain; Brain Infarction; Cells; Central Nervous System Diseases; Cerebral Ventricles; Cerebrovascular system; Cerebrum; Characteristics; Clinical; Clinical Research; Cognitive; Data; Disease; Down-Regulation; Endothelial Growth Factors Receptor; Epidemiology; Female; Financial compensation; Functional disorder; Impaired cognition; Injury; Intracranial Medullary Artery; Investigation; Knowledge; MT3 gene; Modeling; Mus; Myelin; Natural regeneration; Nervous System Physiology; Oligodendroglia; Outcome; Pathologic; Pathology; Patients; Physiological; Play; Population; Prevalence; Recovery; Regenerative response; Research; Role; Signal Transduction; Small Interfering RNA; Syndrome; Testing; Therapeutic; Up-Regulation; VEGF165; Vascular Dementia; Vascular Endothelial Growth Factors; Vascular remodeling; age related; aged; aging brain; aging population; angiogenesis; axon regeneration; brain remodeling; brain repair; cerebral hypoperfusion; cognitive function; density; experimental study; hypoperfusion; improved; insight; male; mouse model; novel; pre-clinical; recruit; repaired; response; stem cells; therapeutic target; vascular cognitive impairment and dementia; white matter

PROJECT SUMMARY/ABSTRACT Subcortical ischemic vascular dementia (SIVD) is the most common subtype of vascular cognitive impairment and dementia (VCID) syndrome that occurs with aging. SIVD is clinically defined as cognitive decline with evidence of subcortical brain infarction. Patients with SIVD suffer from a vast amount of white matter degeneration due to prolonged cerebral hypoperfusion caused by fibrohyalinosis of the medullary artery, and often live with poor neurological function. Although the number of patients with SIVD is predicted to increase with the aging population, to date there is no established treatment for this pathological condition. Since white matter dysfunction is a major characteristic of this disease, most of the mechanistic research in SIVD has focused on oligodendrocyte/myelin damage and blood-brain barrier (BBB) damage within white matter. Although the potential for white matter regeneration and recovery has not been widely studied, compensatory responses for axonal regeneration along with oligodendrogenesis were observed in pre- clinical animal models for SIVD. Therefore, it may be beneficial to recruit vascular remodeling as an approach to support white matter repair/remodeling, which may alleviate the cognitive decline of SIVD patients. Clinical studies indicate that restoring blood flow may improve cognitive function; however, investigations into mechanisms of angiogenesis and vascular remodeling in SIVD are still lacking. This is the major gap in knowledge that we seek to fill. Vascular endothelial growth factor (VEGF) is heavily involved in regulating angiogenesis and vascular (re)formation under both physiological and pathological conditions. However, its role in SIVD is unclear, especially in the aged brain. Therefore, this exploratory study aims to reveal the roles of VEGF signaling in angiogenic responses in cerebral white matter, by testing three hypotheses in a mouse model of SIVD: (i) compensatory angiogenesis and vascular remodeling in SIVD mice is dampened by age, (ii) aged brains have a lowered capacity for angiogenesis due to a decrease in VEGF signaling, and (iii) upregulating VEGF signaling may support vascular repair/remodeling in aged SIVD mice. For testing these hypotheses, we propose 2 integrated aims. Aim 1 will show that aged brain has a lowered capacity for compensatory angiogenesis after cerebral hypoperfusion in mice, and Aim 2 will show that upregulation of VEGF signaling rescues compensatory angiogenesis in aged hypoperfused-SIVD mice. This exploratory study will provide novel insights into the mechanisms by which age-related decline in vascular repair worsens white matter pathology in SIVD, and will provide a proof-of-concept that VEGF signaling is a viable therapeutic target for SIVD.

项目总结/摘要 皮质下缺血性血管性痴呆（SIVD）是血管性认知功能障碍最常见的亚型， 老年痴呆症（VCID）是一种伴随着衰老而发生的疾病。SIVD在临床上被定义为认知障碍 出现皮质下脑梗死SIVD患者患有大量的白色 由于延髓纤维透明变性引起的长时间脑灌注不足导致的物质变性 动脉，并往往生活与神经功能差。尽管预测SIVD患者的数量 随着人口老龄化而增加，迄今为止还没有确定的治疗这种病理性疾病的方法。 条件 由于白色物质功能障碍是这种疾病的主要特征，因此， SIVD主要关注白色脑内的少突胶质细胞/髓鞘损伤和血脑屏障（BBB）损伤。 所谓了虽然白色物质再生和回收的潜力还没有得到广泛的研究， 轴突再生的补偿反应沿着少突胶质细胞的发生。 SIVD的临床动物模型。因此，招募血管重塑作为一种治疗方法可能是有益的。 支持白色修复/重塑的方法，可缓解SIVD的认知下降 患者临床研究表明，恢复血流可以改善认知功能;然而， 但对SIVD中血管生成和血管重塑的机制仍缺乏研究。这是 我们试图填补的主要知识空白。 血管内皮生长因子（VEGF）在很大程度上参与调节血管生成和血管内皮生长。 在生理和病理条件下的（再）形成。然而，它在SIVD中的作用尚不清楚， 特别是在老年人的大脑中。因此，本探索性研究旨在揭示VEGF信号转导在 脑白色物质中的血管生成反应，通过在SIVD小鼠模型中测试三个假设：（i） SIVD小鼠中的补偿性血管生成和血管重塑受到年龄的抑制，（ii）老化的大脑 由于VEGF信号传导的减少而具有降低的血管生成能力，和（iii）上调VEGF 信号传导可以支持老年SIVD小鼠中的血管修复/重塑。 为了验证这些假设，我们提出了两个综合目标。目的1将表明，老年人的大脑有一个降低 小鼠脑灌注不足后代偿性血管生成的能力，Aim 2将显示， VEGF信号传导的上调挽救了老龄低灌注SIVD小鼠中的代偿性血管生成。这 探索性研究将提供新的见解，通过这种机制，年龄相关的血管下降， 修复SIVD的白色病变，并将提供一个概念验证，即VEGF信号转导是SIVD的一个重要机制。 SIVD的可行治疗靶点。