title: Vascular change and opposing effects of the angiotensin type 2 receptor in a mouse model of vascular cognitive impairment.
abstract: Our aims were to assess the spatiotemporal development of brain pathology in a mouse model of chronic hypoperfusion using magnetic resonance imaging (MRI), and to test whether the renin-angiotensin system (RAS) can offer therapeutic benefit. For the first time, different patterns of cerebral blood flow alterations were observed in hypoperfused mice that ranged from an immediate and dramatic to a delayed decrease in cerebral perfusion. Diffusion tensor imaging revealed increases in several quantitative parameters in different brain regions that are indicative of white-matter degeneration; this began around 3 weeks after induction of hypoperfusion. While this model may be more variable than previously reported, neuroimaging tools represent a promising way to identify surrogate markers of pathology. Vascular remodelling was observed in hypoperfused mice, particularly in the anterior part of the Circle of Willis. While the angiotensin II receptor type 2 agonist, Compound 21 (C21), did not influence this response, it did promote expansion of the basilar artery in microcoil animals. Furthermore, C21-treated animals exhibited increased brain lymphocyte infiltration, and importantly, C21 had opposing effects on spatial reference memory in hypoperfused and sham mice. These results suggest that the RAS may have a role in vascular cognitive impairment.
authors.affiliation: 1] Department of Experimental Neurology, Center for Stroke Research Berlin (CSB), Charité Universitätsmedizin Berlin, Berlin, Germany [2] German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Füchtemeier
authors.affiliation: Department of Experimental Neurology, Center for Stroke Research Berlin (CSB), Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Marie P
authors.initials: MP
authors.lastname: Brinckmann
authors.affiliation: Department of Experimental Neurology, Center for Stroke Research Berlin (CSB), Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Foddis
authors.affiliation: Department of Experimental Neurology, Center for Stroke Research Berlin (CSB), Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kunz
authors.affiliation: Imagerie par Résonance Magnétique Médicale et Multi-Modalités, Université Paris Sud, Orsay, France.
authors.forename: Chrystelle
authors.initials: C
authors.lastname: Po
authors.affiliation: 1] German Rheumatism Research Center (DRFZ), A Leibniz Institute, Berlin, Germany [2] Excellence Cluster NeuroCure, Berlin, Germany.
authors.forename: Caterina
authors.initials: C
authors.lastname: Curato
authors.affiliation: 1] Department of Experimental Neurology, Center for Stroke Research Berlin (CSB), Charité Universitätsmedizin Berlin, Berlin, Germany [2] German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany [3] Excellence Cluster NeuroCure, Berlin, Germany [4] German Center for Cardiovasular Diseases (DZHK), Berlin, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Dirnagl
authors.affiliation: Department of Experimental Neurology, Center for Stroke Research Berlin (CSB), Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Tracy D
authors.initials: TD
authors.lastname: Farr
mesh_terms: D057912:Angiotensin II Type 2 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D015140:Dementia, Vascular / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*
chemical_list: D057912:Angiotensin II Type 2 Receptor Blockers; D044139:Receptor, Angiotensin, Type 2