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


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.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.