title: Brain endothelial barrier passage by monocytes is controlled by the endothelin system.
abstract: Homeostasis of the brain is dependent on the blood-brain barrier (BBB). This barrier tightly regulates the exchange of essential nutrients and limits the free flow of immune cells into the CNS. Perturbations of BBB function and the loss of its immune quiescence are hallmarks of a variety of brain diseases, including multiple sclerosis (MS), vascular dementia, and stroke. In particular, diapedesis of monocytes and subsequent trafficking of monocyte-derived macrophages into the brain are key mediators of demyelination and axonal damage in MS. Endothelin-1 (ET-1) is considered as a potent pro-inflammatory peptide and has been implicated in the development of cardiovascular diseases. Here, we studied the role of different components of the endothelin system, i.e., ET-1, its type B receptor (ET(B)) and endothelin-converting enzyme-1 (ECE-1) in monocyte diapedesis of a human brain endothelial cell barrier. Our pharmacological inhibitory and specific gene knockdown studies point to a regulatory function of these proteins in transendothelial passage of monocytes. Results from this study suggest that the endothelin system is a putative target within the brain for anti-inflammatory treatment in neurological diseases.
authors.affiliation: Blood-brain barrier Research Group, Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands. a.reijerkerk@vumc.nl
authors.forename: Arie
authors.initials: A
authors.lastname: Reijerkerk
authors.forename: Kim A M
authors.initials: KA
authors.lastname: Lakeman
authors.forename: Joost A R
authors.initials: JA
authors.lastname: Drexhage
authors.forename: Bert
authors.initials: B
authors.lastname: van Het Hof
authors.forename: Yolanda
authors.initials: Y
authors.lastname: van Wijck
authors.forename: Susanne M A
authors.initials: SM
authors.lastname: van der Pol
authors.forename: Gijs
authors.initials: G
authors.lastname: Kooij
authors.forename: Dirk
authors.initials: D
authors.lastname: Geerts
authors.forename: Helga E
authors.initials: HE
authors.lastname: de Vries
mesh_terms: D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism*; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D008666:Metalloendopeptidases / Q000378:metabolism; D009000:Monocytes / Q000166:cytology*; D017466:Receptors, Endothelin / Q000378:metabolism; D057705:Transendothelial and Transepithelial Migration / Q000502:physiology*
chemical_list: D016232:Endothelins; D017466:Receptors, Endothelin; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes