title: Crosstalk between oligodendrocytes and cerebral endothelium contributes to vascular remodeling after white matter injury.
abstract: After stroke and brain injury, cortical gray matter recovery involves mechanisms of neurovascular matrix remodeling. In white matter, however, the mechanisms of recovery remain unclear. In this study, we demonstrate that oligodendrocytes secrete matrix metalloproteinase-9 (MMP-9), which accelerates the angiogenic response after white matter injury. In primary oligodendrocyte cultures, treatment with the proinflammatory cytokine interleukin-1β (IL-1β) induced an upregulation and secretion of MMP-9. Conditioned media from IL-1β-stimulated oligodendrocytes significantly amplified matrigel tube formation in brain endothelial cells, indicating that MMP-9 from oligodendrocytes can promote angiogenesis in vitro. Next, we asked whether similar signals and substrates operate after white matter injury in vivo. Focal white matter injury and demyelination was induced in mice via stereotactic injection of lysophosphatidylcholine into corpus callosum. Western blot analysis showed that IL-1β expression was increased in damaged white matter. Immunostaining demonstrated MMP-9 signals in myelin-associated oligodendrocytic basic protein-positive oligodendrocytes. Treatment with an IL-1β-neutralizing antibody suppressed the MMP-9 response in oligodendrocytes. Finally, we confirmed that the broad spectrum MMP inhibitor GM6001 inhibited angiogenesis around the injury area in this white matter injury model. In gray matter, a neurovascular niche promotes cortical recovery after brain injury. Our study suggests that an analogous oligovascular niche may mediate recovery in white matter.
authors.affiliation: Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Loc-Duyen D
authors.initials: LD
authors.lastname: Pham
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Hayakawa
authors.forename: Ji Hae
authors.initials: JH
authors.lastname: Seo
authors.forename: Minh-Nguyet
authors.initials: MN
authors.lastname: Nguyen
authors.forename: Angel T
authors.initials: AT
authors.lastname: Som
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Lee
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Guo
authors.forename: Kyu-Won
authors.initials: KW
authors.lastname: Kim
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.forename: Ken
authors.initials: K
authors.lastname: Arai
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001930:Brain Injuries / Q000473:pathology / Q000503:physiopathology*; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D004727:Endothelium / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D053583:Interleukin-1beta / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D004676:Myelin Basic Protein / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D017077:Culture Media, Conditioned; D004151:Dipeptides; D053583:Interleukin-1beta; D007770:L-Lactate Dehydrogenase; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011480:Protease Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; C522729:Olig2 protein, rat