Leveraging doppler ultrasound imaging to measure pulse wave velocity changes in a mouse model of arterial stiffening to elucidate molecular pathways underlying cerebral damage

Abstract

AbstractBackgroundThe highly vascularized brain is particularly vulnerable to changes in pulsatility of blood flow. With age, elastin in arteries breaks down and is replaced by collagen, making arteries less compliant and resulting in arterial stiffening. Stiffening alters pulsatility, which can be measured by pulse wave velocity (PWV), and damages small capillary beds and the neurovascular unit (NVU). The NVU is essential for proper delivery of oxygen and nutrients to the brain. Human studies have demonstrated associations between increased arterial stiffness and biomarkers of Alzheimer’s disease (AD) and neurodegeneration. We adapted a doppler ultrasound imaging method previously only used in rats to measure PWV in a mouse model of arterial stiffening to advance our understanding of the molecular underpinnings of AD and neurodegeneration.Method7‐month‐old, C57BL/6, male and female mice underwent a carotid calcification surgery, where the carotid artery was exposed to 0.3 mol/L CaCl2 (or saline as a control) for 20 minutes. PWV was measured using doppler ultrasound imaging before and after surgery. Two weeks post‐surgery, mice underwent behavioral testing, including locomotor activity, elevated zero maze, Barnes maze, and nest building. Collagen, calcium, and elastin levels in the carotid artery were determined 4 weeks post‐surgery by immunohistochemistry.ResultPreliminary results demonstrate the carotid calcification surgery successfully increased PWV in mice three weeks post‐surgery. Surgery did not inhibit behavioral task performances two weeks post‐operative. Additional data collection is underway applying this method in two transgenic AD mouse models, APP/PSEN1 and P301S, which will include behavioral testing and histological assessment of NVU components, specifically endothelial cells (CD31/PECAM), pericytes (PDGRFb), and astrocytes (GFAP) in the hippocampus.ConclusionElucidating a clear molecular link between increased arterial stiffness and cognition is essential to understanding how age‐related changes in systemic blood flow may influence AD pathology and neurodegeneration. Our preliminary results demonstrate that doppler ultrasound imaging, previously only used in rats, can be applied in mice as a reliable measurement of PWV. We will leverage this model to test the hypothesis that increased PWV is associated with worse spatial learning and memory, impaired functioning of the NVU, and increased AD pathology.