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.

项目概要/摘要 皮质下缺血性血管性痴呆（SIVD）是血管性认知障碍最常见的亚型 随着衰老而发生的损伤和痴呆（VCID）综合征。 SIVD在临床上被定义为认知 有皮质下脑梗死证据的情况下下降。 SIVD 患者患有大量白细胞 髓质纤维透明变性引起的长期脑灌注不足导致的物质变性 动脉，并且经常生活在神经功能较差的情况下。尽管预计 SIVD 患者数量 随着人口老龄化的加剧，迄今为止还没有针对这种病理学的既定治疗方法 健康）状况。 由于白质功能障碍是该疾病的主要特征，因此大多数机制研究 SIVD 重点关注白细胞内的少突胶质细胞/髓磷脂损伤和血脑屏障 (BBB) 损伤 事情。尽管白质再生和恢复的潜力尚未得到广泛研究， 在预-观察到轴突再生和少突胶质细胞发生的代偿反应 SIVD 的临床动物模型。因此，招募血管重塑作为一种可能是有益的。 支持白质修复/重塑的方法，可能会减轻 SIVD 的认知衰退 患者。临床研究表明，恢复血流可以改善认知功能；然而， 目前仍缺乏对 SIVD 中血管生成和血管重塑机制的研究。这是 我们寻求填补的主要知识空白。 血管内皮生长因子（VEGF）在调节血管生成和血管生成方面发挥着重要作用。 在生理和病理条件下（重新）形成。然而，其在 SIVD 中的作用尚不清楚， 尤其是在老年人的大脑中。因此，本探索性研究旨在揭示 VEGF 信号在 通过在 SIVD 小鼠模型中测试三个假设，研究大脑白质中的血管生成反应：(i) SIVD 小鼠的代偿性血管生成和血管重塑会因年龄而减弱，(ii) 大脑老化 由于 VEGF 信号传导减弱，血管生成能力降低，并且 (iii) 上调 VEGF 信号传导可能支持老年 SIVD 小鼠的血管修复/重塑。 为了检验这些假设，我们提出了 2 个综合目标。目标 1 将表明，老年人的大脑功能降低 小鼠脑灌注不足后代偿性血管生成的能力，目标 2 将表明 VEGF 信号传导的上调可挽救老年低灌注 SIVD 小鼠的代偿性血管生成。这 探索性研究将为年龄相关的血管衰退的机制提供新的见解 修复使 SIVD 中的白质病理恶化，并将提供 VEGF 信号传导是一种概念验证。 SIVD 的可行治疗靶点。