Angiotensin II Type 2 Receptor Agonism Alleviates Progressive Post-stroke Cognitive Impairment in Aged Spontaneously Hypertensive Rats

Hypertension and aging are leading risk factors for stroke and vascular contributions to cognitive impairment and dementia (VCID). Most animal models fail to capture the complex interplay between these pathophysiological processes. In the current study, we examined the development of cognitive impairment in 18-month-old spontaneously hypertensive rats (SHR) before and following ischemic stroke. Sixty SHRs were housed for 18 months with cognitive assessments every 6 months and post-surgery. MRI scans were performed at baseline and throughout the study. On day 3 post-stroke, rats were randomized to receive either angiotensin II type 2 receptor (AT2R) agonist Compound 21 (C21) or plain water for 8 weeks. SHRs demonstrated a progressive cognitive decline and significant MRI abnormalities before stroke. Perioperative mortality within 72 h of stroke was low. Stroke resulted in significant acute brain swelling, chronic brain atrophy, and sustained sensorimotor and behavioral deficits. There was no evidence of anhedonia at week 8. C21 enhanced sensorimotor recovery and ischemic lesion resolution at week 8. SHRs represent a clinically relevant animal model to study aging and stroke-associated VCID. This study underscores the importance of translational disease modeling and provides evidence that modulation of the AT2R signaling via C21 may be a useful therapeutic option to improve sensorimotor and cognitive outcomes even in aged animals.