A novel therapeutic Ang(1-7) analogue improves neurovascular function in mice with vascular contributions to cognitive impairment and dementia

Dynamic cerebral blood flow (CBF) regulation via neurovascular coupling (NVC) is essential to meet localized brain oxygen and nutrient demands. Cerebral microvascular dysfunction contributes to the pathogenesis of many types of dementias. Previous studies suggest that oxidative stress play a critical role in endothelial disfunction, cerebral microvascular impairments, and blunted NVC responses. Increased reactive oxidative species (ROS), inflammatory cytokines, and decreased brain blood flow contribute to the progression of both vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer's disease related dementia (ADRD).Our novel synthetic glycosylated Angiotensin-(1-7) derivative, PNA5, reverses cognitive deficits, inhibits brain ROS and inflammatory cytokine production, and limits microglial activation in our preclinical model of heart failure (HF)-induced VCID. We hypothesize that heart failure (HF) impairs cerebral vascular dilation and NVC, and that treatment with extended release PNA5 (PNA5ER) will improved cerebral vascular dilation and NVC. Adult male C57BL/6J mice (6-10/group) were subjected to HF via left anterior artery ligation or sham surgery 5 weeks prior to treatment with either 1) Vehicle (DMSO) or 2) 1.5mg PNA5ER (30uL of 50 mg/mL). Treatments were delivered subcutaneously at time= 3 weeks and again at t= 1 week prior to vascular evaluation and sacrifice. NVC was assessed using laser speckle imaging. Basal cerebral perfusion and NVC after somatosensory stimulation were assessed by laser speckle contrast imaging. NVC was calculated as a percent change in perfusion from baseline induced by stimulation. Basilar arteries were mounted on a wire myograph to assess cerebral vascular function. HF mice receiving vehicle treatment (n=2, mean= 4.41, Std Deviation=2.32) trend to have decreased NVC response compared to Sham (n=5, mean= 13.63, Std Deviation= 10.35), which may be rescued by PNA5ER (n=3, mean= 10.32, Std Deviation= 4.499). Endothelium-dependent dilation of basilar arteries, induced by cumulative concentrations of NS309 and 2-Methylthio-ADP, was impaired in HF compared to Sham mice; PNA5ER improved vasodilatory responses in the basilar artery.Our preliminary data suggest that PNA5ER protects against NVC impairments and improves basilar artery vasodilation in mice with HF-induced VCID, thereby potentially increasing the ability of the vasculature to meet the localized metabolic demands of the brain. Supported by NIA This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.