title: Vascular dysfunction in a mouse model of Rett syndrome and effects of curcumin treatment.
abstract: Mutations in the coding sequence of the X-linked gene MeCP2 (Methyl CpG-binding protein) are present in around 80% of patients with Rett Syndrome, a common cause of intellectual disability in female and to date without any effective pharmacological treatment. A relevant, and so far unexplored feature of RTT patients, is a marked reduction in peripheral circulation. To investigate the relationship between loss of MeCP2 and this clinical aspect, we used the MeCP2 null mouse model B6.129SF1-MeCP2tm1Jae for functional and pharmacological studies. Functional experiments were performed on isolated resistance mesenteric vessels, mounted on a pressurized myograph. Vessels from female MeCP2(+/-) mice show a reduced endothelium-dependent relaxation, due to a reduced Nitric Oxide (NO) availability secondary to an increased Reactive Oxygen Species (ROS) generation. Such functional aspects are associated with an intravascular increase in superoxide anion production, and a decreased vascular eNOS expression. These alterations are reversed by curcumin administration (5% (w/w) dietary curcumin for 21 days), which restores endothelial NO availability, decreases intravascular ROS production and normalizes vascular eNOS gene expression. In conclusion our findings highlight alterations in the vascular/endothelial system in the absence of a correct function of MeCP2, and uncover related cellular/molecular mechanisms that are rescued by an anti-oxidant treatment.
authors.affiliation: Institute of Neuroscience, Italian National Research Council (CNR), Pisa, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Panighini
authors.forename: Emiliano
authors.initials: E
authors.lastname: Duranti
authors.forename: Ferruccio
authors.initials: F
authors.lastname: Santini
authors.forename: Margherita
authors.initials: M
authors.lastname: Maffei
authors.forename: Tommaso
authors.initials: T
authors.lastname: Pizzorusso
authors.forename: Niccola
authors.initials: N
authors.lastname: Funel
authors.forename: Stefano
authors.initials: S
authors.lastname: Taddei
authors.forename: Nunzia
authors.initials: N
authors.lastname: Bernardini
authors.forename: Chiara
authors.initials: C
authors.lastname: Ippolito
authors.forename: Agostino
authors.initials: A
authors.lastname: Virdis
authors.forename: Mario
authors.initials: M
authors.lastname: Costa
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000503:physiopathology*; D003474:Curcumin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007150:Immunohistochemistry; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015518:Rett Syndrome / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014652:Vascular Diseases / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*
chemical_list: D012333:RNA, Messenger; D013481:Superoxides; D008315:Malondialdehyde; D052250:Nitric Oxide Synthase Type III; D003474:Curcumin