Perenkita J. Mendiola, Philip O’Herron, Kun, Xie, Valeria Di Stefano, Michael W. Brands, Jessica A. Filosa. Department of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia, USA

A growing body of evidence underscores the significance of elevated blood pressure variability (BPV) as an emerging risk factor for cardiovascular events, cognitive decline, and end-organ damage. Yet, the specific cellular targets and underlying mechanisms governing intravascular pressure fluctuations-induced neuronal dysfunction remain elusive. To address this critical knowledge gap, we developed an innovative murine model of BPV.

Our study aims to determine the impact of chronic BPV on neurovascular-dependent processes, encompassing both steady-state and stimulus-evoked alterations in cerebral blood flow. Middel aged mice (12-15 months old) underwent surgical implantation of a chronic cranial window, and were injected with an AAV5-GCaMP6f virus to facilitate the monitoring of cortical astrocyte Ca²⁺ events. Mice were then equipped with a programmable infusion pump and telemetry transmitter. Intermittent Angiotensin II (Ang II) infusions induced blood pressure (BP) fluctuations, effectively increasing the average real variability (P<0.02) and coefficient of variation (P<0.0001). Notably, the chronic BPV protocol (20-25 days) did not induce hypertension but did attenuate the bradycardic reflex response to Ang II-evoked increases in blood pressure (P<0.03).

Following 20 days of BPV, we assessed parenchymal arteriole diameter responses to Ang II-induced pressure increases using two-photon imaging. In the same mouse, we also measured the sensory-evoked response (whisker stimulation) when the pump was off (low-BP period) and during the Ang II infusion (high-BP period). Mice subjected to chronic BPV exhibited blunted myogenic-induced constrictions (P<0.04). In control mice, sensory-evoked responses displayed a significant pressure dependency (P<0.0001), with a greater response during higher mean arterial pressure (~92 mmHg vs 78 mmHg); this pressure dependency was significantly compromised (P<0.002) in the BPV group. Contrary to our expectations, acute pressure increases in BPV mice exhibited no changes in the magnitude of the astrocyte Ca²⁺ response but a significant increase in the frequency of the Ca²⁺ events (P<0.01).

In summary, chronic BPV led to a substantial decrease in the ability of parenchymal arterioles to respond to acute pressure increases, a blunted neurovascular coupling response, and altered astrocyte Ca²⁺ dynamics. These findings collectively support the hypothesis that increased BPV detrimentally affects elements of the neurovascular unit, representing a likely early event contributing to cognitive decline.