title: Constitutive excessive erythrocytosis causes inflammation and increased vascular permeability in aged mouse brain.
abstract: Excessive erythrocytosis results in severely increased blood viscosity that may compromise the vascular endothelium. Using our transgenic mouse model of excessive erythrocytosis we previously showed that despite altered brain endothelial cell morphology and an activated vasculature, brain vascular integrity was largely maintained up to 4-5 months of age. We now present data showing that persistent long-term damage of the vascular wall during the later stages of adulthood (9-12 months) results in a chronic detrimental inflammatory phenotype and increased vessel permeability that likely contributes to the reduced life span of our erythropoietin overexpressing transgenic mouse. In aged transgenic animals inflammatory cells were detected in brain tissue and elevated RNA and protein levels of inflammatory markers such as IL-6 and TNFα were observed in both brain tissue and blood plasma. Additionally, increased expression of p53 and other pro-apoptotic markers, as well as decreased Bcl-xL expression in the brain vasculature, indicated ongoing cell death within the vascular compartment. Finally, abnormally elevated vascular permeability in all organs was detected in correlation with decreased expression of the tight junction protein occludin and the adherens junction protein β-catenin in brain. Thus chronic erythrocytosis results in sustained activation of inflammatory pathways, vascular dysfunction and blood-brain barrier disruption.
authors.affiliation: Institute of Veterinary Physiology, Vetsuisse Faculty and Zurich Center for Integrative Human Physiology (ZIHP), University of Zürich, Switzerland. Larao@access.uzh.ch
authors.forename: O O
authors.initials: OO
authors.lastname: Ogunshola
authors.forename: M
authors.initials: M
authors.lastname: Moransard
authors.forename: M
authors.initials: M
authors.lastname: Gassmann
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D002199:Capillary Permeability / Q000502:physiology*; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011086:Polycythemia / Q000378:metabolism* / Q000473:pathology
chemical_list: D018836:Inflammation Mediators
keywords: Cell death; Endothelial activation; Endothelium; Erythropoietin