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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

基本信息

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
项目类别：
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

项目摘要

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/文摘