Targeting RBC dysfunction in VCID

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Red blood cell (RBC) dysfunction may play a major role in VCID. The RBC expresses NOS3 (eryNOS3), a key mediator of cerebral blood flow (CBF). Our long-term goal is to target RBC dysfunction (rheoerythrocrine) in patients with cerebral small vessel disease (SVD) and white matter (WM) damage, an unexplored area in dementia and VCID research. We advance the provocative hypothesis that age-related RBC dysfunction with reduced eryNOS3 and eryNO coupled with underlying endothelial dysfunction leads to reduced CBF, WM damage and cognitive impairment. A secondary hypothesis is that this RBC dysfunction can be targeted and ameliorated with physical exercise and chronic remote ischemic conditioning (C-RIC), an exercise mimetic. Our Specific Aims are: Aim 1. (Mice) Determine the contribution of the dose of eryNOS3 to WM damage, CBF, and cognitive outcomes in the bilateral carotid artery stenosis (BCAS) model. We will utilize male, female, and aged mutant mice lacking NOS3 in the erythroid lineage (eryNOS3-/- ) Aim 2. (Mice-Therapeutic) Determine if modulating and improving RBC dysfunction with C-RIC and/or physical exercise will improve cognition, reduce WM damage and improved functional outcomes. Aim 3. ( Human) Determine if C-RIC targets and improves RBC rheoerythrocrine biomarkers in human subjects with VCID and WM disease. .