Abstract 083: Neurovascular And Cognitive Dysfunction In Middle-Aged Mice With High Blood Pressure Variability

Abstract

Blood pressure variability (BPV) is a novel risk factor for cognitive decline. This study tested the hypothesis that BPV disrupts cellular function and communication at the neurovascular complex (vascular, glia, and neuron) contributing to BPV-induced neurovascular dysfunction. A main goal of the study was to establish a murine BPV model and examine how this risk factor impacts key functional outputs of the neurovascular complex. Middle-aged C57BL6 mice were implanted a cranial window and injected GCaMP viral vectors to monitor Ca 2+ activity in cortical neurons or astrocytes. DSI telemetry was used to monitor cardiovascular variables simultaneously ( in vivo ) with arteriole diameter and astrocyte/neuronal Ca 2+ responses via two-photon imaging. In addition, mice were implanted a programmable pump and infused 6-8 pulses/day of saline (Control) or angiotensin II (Ang II, 18 μg/day) for 20-25 days. Ang II infusions evoked transient BP increases (Δ 23±2 mmHg, mean arterial pressure (MAP, P=0.0001, n=14)), and increased BPV (P=0.04, n=12) measured by the average real variability. The 24-hour MAP was not different compared to Controls, allowing for the investigation of BPV-evoked changes in neurovascular function in the absence of hypertension. BPV mice displayed cognitive decline (NOR, P=0.006, n=10). Myogenic responses were lost in parenchymal arterioles of BPV mice but preserved in Controls (P<0.01 n=6). In addition to impaired vascular function, during Ang II-induced BP increases, astrocytes of BPV mice exhibited greater Ca 2+ event frequency (P<0.0001, n=4-6), but of lesser amplitude and reduced area (P=0.02, n=4-6). Furthermore, the neurovascular coupling response, evoked via whisker stimulation, was blunted in mice with high BPV (P<0.0001, n=6-10). Relevant to inflammation, microglial cells from BPV mice had elevated Iba1 (P=0.03, n=4-5) and CD68+ (P=0.003), an inflammatory marker. These findings show that BPV, in the absence of hypertension, result in a loss of cerebral autoregulation, a shift in spontaneous astrocyte Ca 2+ dynamics during blood pressure fluctuations, and increased microglia reactivity. Future mechanistic studies are needed to determine how BPV contributes to cognitive decline.