Cognitive Decline in a Mouse Model of Arterial Stiffening is Associated with Microgliosis and Reduced Resting Cerebral Blood Flow

Dementia currently affects approximately 50 million adults worldwide and is a leading contributor to mortality and disability. Cardiovascular risk factors, such as hypertension and increase arterial stiffening, are recognized as important contributors to dementia. Aortic stiffening in humans is linked to cognitive deficits and biomarkers of neurodegeneration; however, the molecular mechanisms underlying this effect remain largely unexplored. The objective of this study is to address how arterial stiffness affects cognitive function. We hypothesize that arterial stiffening induces neuroinflammation and reduces cerebral blood flow (CBF), which synergistically promote cognitive impairment. To test this hypothesis, we induced a brief episode of hypertension by a two-week s.c. infusion of angiotensin II (Ang II; 600ng/kg/min) via osmotic mini pumps in 3-month-old male C57BL/6 mice. Blood pressure was measured twice per week by tail-cuff plethysmography. Systolic blood pressure increased during the Ang II infusion (Ang II: 141.8 vs saline: 110.7 mmHg; n=10 mice/group; p<0.0001) and returned to normal after pump removal on day 14 of infusion (124.8 ± 4.367 mmHg). Previous studies have established that extensive aortic stiffening develops in the months following Ang II infusion. To test whether arterial stiffening leads to cognitive impairment, we evaluated cognitive function at 1, 2, and 3 months following the Ang II infusion. We employed a battery of neurobehavioral assays (n=11-16 mice/group) to assess various cognitive domains, including spatial working memory (Y-maze), recognition memory (Novel Object Recognition), spatial learning and memory (Barnes maze), and activities of daily life (Nest Building). We found that exposure of Ang II leads to deficits in spatial, recognition, and long-term memory at 2 months post-infusion as evidenced by a reduction in spontaneous alternations in the Y-maze (Ang II: 52.44 ± 3.09 vs saline: 63.00 ± 2.53; p=0.0088), reduction in the discrimination index between the novel and familiar objects (Ang II: 0.1248 ± 0.046 vs saline: 0.3478 ± 0.074; p=0.0354, and less time spent in the target quadrant where the escape hole used to be in the Barnes maze probe trial (Ang II: 60.57 ± 4.76 vs saline: 78.98 ± 3.79 %; p=0.0060). Next, we assessed whether arterial stiffening impaired absolute resting cerebral blood flow (CBF), measured by arterial spin labeling (ASL)-MRI, two months after Ang II infusion. Here, we observed a drastic reduction in CBF in both the cortex and the hippocampus, areas important for learning and memory. Lastly, we were interested whether arterial stiffening promoted neuroinflammation in the cortex and hippocampus. To this end, we performed immunohistochemistry for microglia (Iba1) and astrocytes (GFAP) to determine the presence of gliosis. Here, we found increased microglia density in the cortex of mice after 3 months of Ang II infusion compared to the saline. In conclusion, our study finds that arterial stiffening induced by a brief episode of hypertension causes cognitive impairment associated with a reduction in CBF and concomitant gliosis in the brain’s memory centers. NIH K22 NS123507 and Alzheimer's Association AARGD-24-1293605 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.