Abstract P233: Mas Receptor Deficiency Does Not Impair Cognitive Funcion of Vascular Dementia Model in the Presence of Angiotensin II Type 2 Receptor

Abstract

Objective: Angiotensin (Ang) converting enzyme (ACE) 2/ Ang-(1-7)/Mas receptor axis has been considered as protective arm in the renin-angiotensin system and Ang-(1-7) is thought to interact with Ang II type 2 (AT 2 ) receptor according. Mas receptor is expressed highly in hippocampus and blood vessels in brain, but its actual function is still unclear. Thus, we examined the possible roles of Mas receptor in relation to the vascular cognitive impairment focusing on the interaction with AT 2 receptor. Design and Methods: Male 10-week-old C57BL6 mice (wild-type, WT), Mas1 receptor knockout mice (MasKO) and AT 2 /Mas1 receptor double knockout mice (DKO) were subjected to bilateral carotid artery stenosis (BCAS) surgery. After six weeks from the treatment, we evaluated their cognitive function with Y-maze test and the Morris water maze test. Results: The cerebral blood flow (CBF) in each BCAS group was significantly reduced compared to its sham-operated counterparts (WT; 31.5±0.6 vs 28.0±0.8, MasKO; 31.7±0.8 vs 27.7±0.8, DKO; 33.0±0.5 vs 29.1±0.7). The alternation behavior (%) was significantly reduced in WT mice with BCAS compared to sham mice (69.6±3.5 vs 57.9±2.1), but there was no significant difference in MasKO and DKO mice (MasKO; 64.1±2.5 vs 63.1±2.5, DKO; 67.6±2.1 vs 61.1±4.0) in Y maze test. In the Morris water maze test, the mean arrival time at platform at day 5 (sec) was significantly higher in WT-BCAS mice than WT-sham mice (Sham; 20.9±4.6 vs BCAS; 47.3±6.5). In contrast to the results in WT, there was no significant difference in MasKO mice (Sham; 32.8±8.5 vs BCAS; 34.5±7.3). DKO-sham mice showed significantly lower spatial learning ability compared with WT-sham mice (DKO; 77.4±11.9 vs WT; 20.9±4.6). The total cell count in dentate gyrus area was significantly lower in WT-BCAS compared to WT-sham (sham; 255.7±7.0 vs BCAS; 209.4±5.4), but there was no significant change in MasKO mice(sham; 256.5±2.5 vs BCAS; 233.2±16.4). We could not see significant difference in the number of DCX-positive cells and the expressions of proinflammatory cytokines such as IL-6, TNF-α and MCP-1in all mouse groups. Conclusion: Mas receptor deficiency seems to be beneficial in vascular dementia on condition that AT 2 receptor exists.