title: Astrocyte-derived thrombospondin-2 is critical for the repair of the blood-brain barrier.
abstract: Thrombospondin (TSP)-2-null mice have an altered brain foreign body response (FBR) characterized by increases in inflammation, extracellular matrix deposition, and leakage of the blood-brain barrier (BBB). In the present study, we investigated the role of TSP-2 in BBB repair during the brain FBR to mixed cellulose ester filters implanted in the cortex of wild-type (WT) and TSP-2-null mice for 2 days to 8 weeks. Histological and immunohistochemical analysis revealed enhanced and prolonged neuroinflammation in TSP-2-null mice up to 8 weeks after implantation. In addition, recovery of the BBB was compromised and was associated with increased gelatinolytic activity and low levels of collagen type IV in the basement membranes of TSP-2-null blood vessels. An analysis of protein extracts from implantation sites revealed elevated levels of matrix metalloproteinase (MMP)-2 and MMP-9 in TSP-2-null brains. TSP-2-null astrocytes secreted higher levels of both MMPs in vitro compared with their WT counterparts. Furthermore, TSP-2-null astrocytes were deficient in supporting the recovery of barrier function in WT endothelial cells. Finally, Western blot analysis of astrocytes and brain endothelial cells revealed TSP-2 expression only in the former. Taken together, our observations suggest that astrocyte-derived TSP-2 is critical for the maintenance of physiological MMP-2 and MMP-9 levels during the FBR and contributes to the repair of the BBB.
authors.affiliation: Vascular Biology and Therapeutics Program, the Department of Pathology, Yale University, New Haven, Connecticut 06520, USA.
authors.forename: Weiming
authors.initials: W
authors.lastname: Tian
authors.forename: Andrew
authors.initials: A
authors.lastname: Sawyer
authors.forename: Feriha B
authors.initials: FB
authors.lastname: Kocaoglu
authors.forename: Themis R
authors.initials: TR
authors.lastname: Kyriakides
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology*; D001672:Biocompatible Materials; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002560:Cerebrovascular Circulation; D008264:Macrophages / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation; D017628:Microglia / Q000378:metabolism; D012709:Serum Albumin / Q000378:metabolism; D019699:Thrombospondins / Q000378:metabolism*; D013997:Time Factors; D000099262:Thrombospondin 2
chemical_list: D001672:Biocompatible Materials; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D012709:Serum Albumin; D019699:Thrombospondins; D000099262:Thrombospondin 2