title: Elevated levels of homocysteine compromise blood-brain barrier integrity in mice.
abstract: Elevated levels of plasma homocysteine (Hcy) correlate with increased risk of cardiovascular and Alzheimer diseases. We studied the effect of elevated Hcy on the blood-brain barrier (BBB) to explore the possibility of a vascular link between the 2 diseases. On a hyperhomocysteinemic diet, cystathionine beta-synthase (Cbs)-heterozygous mice develop hyperhomocysteinemia. Intravital microscopy analysis of the mesenteric venules showed that leukocyte rolling velocity was markedly decreased and numbers of adherent cells were increased in the mutant mice. This was due at least in part to increased expression of P-selectin. BBB permeability was measured by Evans blue dye permeation and was found to be 25% greater in the Cbs(+/-) cortex compared with wild-type controls. Our study suggests an important toxic effect of elevated Hcy on brain microvessels and implicates Hcy in the disruption of the BBB.
authors.affiliation: CBR Institute for Biomedical Research, 800 Huntington Ave, Boston, MA 02115, USA.
authors.forename: Atul F
authors.initials: AF
authors.lastname: Kamath
authors.forename: Anil K
authors.initials: AK
authors.lastname: Chauhan
authors.forename: Janka
authors.initials: J
authors.lastname: Kisucka
authors.forename: Vandana S
authors.initials: VS
authors.lastname: Dole
authors.forename: Joseph
authors.initials: J
authors.lastname: Loscalzo
authors.forename: Diane E
authors.initials: DE
authors.lastname: Handy
authors.forename: Denisa D
authors.initials: DD
authors.lastname: Wagner
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000098:blood supply* / Q000473:pathology*; D002448:Cell Adhesion; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000502:physiology*; D004032:Diet; D005070:Evans Blue; D006579:Heterozygote; D006710:Homocysteine / Q000097:blood*; D020138:Hyperhomocysteinemia; D007962:Leukocytes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019007:P-Selectin / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D019007:P-Selectin; D006710:Homocysteine; D005070:Evans Blue; D003541:Cystathionine beta-Synthase