Abstract WMP78: The Efficacy of Angiotensin II Peptide Vaccination Against White Matter Lesions of Vascular Dementia in Rats

Background & Purposes: There had been no attempt to show the efficacy of therapeutic vaccination in vascular dementia. A rat model of vascular dementia was prepared by bilateral common carotid artery ligation (2VO). The purpose of this study is to investigate whether pre-exposure Angiotensin II (Ang II) peptide vaccination exhibits the protective effects against white matter lesions (WML) in 2VO rats. Methods: After subcutaneous injection of Ang II peptide vaccine (10μg/200μl) or saline (200μl) to Wistar rats (male) at the time point of 6, 8 and 10 week-old, 2VO or sham surgery was performed at 12 week-old. Cognitive function was evaluated after 14 days of 2VO using the novel object recognition (NOR) test. Anti-Ang II antibody (Ab) level was quantified using ELISA. Histological examinations of WML and demyelination in the corpus callosum (CC) were evaluated using immunohistochemistry (IHC), 5-bromodeoxyuridine (BrdU) assay and Klüver-Barrera staining. Western blot analyses of VCAM-1, FGF2, phospho-CREB and CREB using proteins extracted from CC were performed to investigate the mechanism of restoration of WML by Ang II vaccination. Results: Histological examinations presented that exacerbation of WML and demyelination observed in saline treated (S) rats was ameliorated in Ang II vaccinated (V) rats. The results of NOR test indicated that cognitive dysfunction observed in S rats was improved in V rats at 14 days after 2VO. Expression of VCAM-1 in CC of S rats was significantly reduced in V rats at 7 days after 2VO. BrdU assay exhibited that vaccination accelerated the differentiation of oligodendrocyte progenitor cells (OPCs) in WML from 14 days to 28 days of 2VO. Western blot presented that both CREB phosphorylation and FGF2 expression in CC were increased in V rats compared with S rats at 14 days after 2VO. Double IHC showed that FGF2 expressing cells were mostly endothelial cells and astrocytes in WML. Conclusions: Ang II vaccination restored WML as well as cognitive function in 2VO rats. Our findings suggested that Ang II vaccination ameliorated cerebrovascular endothelial dysfunction which could accelerate the OPCs differentiation through increased expression of FGF2 in endothelial cells or astrocytes in 2VO rats.