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

项目摘要/摘要 皮质下缺血性血管性痴呆(SIVD)是最常见的血管认知亚型 随着年龄增长而出现的损害和痴呆(VCID)综合征。SIVD在临床上被定义为认知 随着皮质下脑梗塞的证据而下降。SIVD患者患有大量的白质 延迟性脑低灌注所致的物质变性 动脉受累，常伴有神经功能低下。尽管预计SIVD患者的数量 随着人口老龄化而增加，到目前为止还没有确定的治疗这种疾病的方法 条件。 由于白质功能障碍是这种疾病的主要特征，大多数机制研究在 SIVD的重点是少突胶质细胞/髓鞘损伤和血脑屏障(BBB)损伤。 物质。尽管白质再生和恢复的潜力还没有得到广泛的研究， 轴突再生和少突胶质细胞形成的代偿性反应在 SIVD的临床动物模型。因此，招募血管重塑作为一种 支持脑白质修复/重塑的方法，可能缓解SIVD的认知功能下降 病人。临床研究表明，恢复血流可能会改善认知功能；然而， 目前尚缺乏对SIVD血管生成和血管重塑机制的研究。这是 我们试图填补的主要知识缺口。 血管内皮生长因子(VEGF)在调节血管生成和血管生成中发挥重要作用 (重新)在生理和病理条件下形成。然而，它在SIVD中的作用尚不清楚， 尤其是在衰老的大脑中。因此，本探索性研究旨在揭示血管内皮细胞生长因子信号转导通路在血管内皮细胞生长中的作用。 通过在SIVD小鼠模型中检验三种假说，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受到年龄的抑制，(Ii)脑老化 由于血管内皮生长因子信号的减少，血管生成能力降低，以及(Iii)上调血管内皮生长因子 信号可能支持老年SIVD小鼠的血管修复/重塑。 为了验证这些假设，我们提出了两个综合目标。目标1将表明，衰老的大脑具有更低的 小鼠脑低灌流后的代偿性血管生成能力，以及目标2将表明 上调血管内皮生长因子信号可挽救老年低灌注型SIVD小鼠的代偿性血管生成。这 探索性研究将为年龄相关性血管功能下降的机制提供新的见解 修复恶化了SIVD的脑白质病理，并将提供一个概念证据，即血管内皮生长因子信号是一种 SIVD的可行治疗靶点。

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.