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.

项目摘要/摘要 皮层缺血性血管痴呆（SIVD）是血管认知最常见的亚型 随着衰老而发生的障碍和痴呆（VCID）综合征。 SIVD在临床上定义为认知 衰落的脑皮层脑梗塞的证据。 SIVD患者患有大量白色 由于髓质的纤维甲胺病引起的长时间脑灌注不足导致的物质变性 动脉，通常具有神经功能不佳的生活。尽管预计患有SIVD的患者数量 为了随着老龄化的人口而增加，迄今为止尚无对这种病理的既定治疗 健康）状况。 由于白质功能障碍是该疾病的主要特征，因此大多数机械研究 SIVD专注于少突胶质细胞/髓鞘损伤和白色的血脑屏障（BBB）损害 事情。尽管尚未广泛研究白质再生和恢复的潜力，但 在前轴突再生以及寡聚的补偿性反应以及 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 支持白质维修/改建的方法，这可能减轻SIVD的认知能力下降 患者。临床研究表明，恢复血流可以改善认知功能。然而， 仍然缺乏对SIVD中血管生成和血管重塑机制的研究。这是 我们寻求填补的知识的主要差距。 血管内皮生长因子（VEGF）大量参与调节血管生成和血管 （重新）在生理和病理条件下形成。但是，其在SIVD中的作用尚不清楚， 特别是在老年大脑中。因此，这项探索性研究旨在揭示VEGF信号在 脑白质中的血管生成反应，通过在SIVD小鼠模型中检验三个假设：（i） SIVD小鼠中的补偿性血管生成和血管重塑会随着年龄而抑制（II）大脑 由于VEGF信号传导的降低，并且（iii）上调VEGF，血管生成能力降低 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个综合目的。 AIM 1将表明衰老的大脑降低 小鼠脑灌注灌注后补偿性血管生成的能力，AIM 2将表明 VEGF信号传导的上调挽救了老化的炎症性sivd小鼠的补偿性血管生成。这 探索性研究将提供有关血管相关年龄相关的机制的新见解 维修恶化了SIVD中的白质病理学，并将提供概念证明VEGF信号是一种 SIVD的可行治疗靶标。