Microvascular damage, neuroinflammation and extracellular matrix remodeling in Col18a1 knockout mice as a model for early cerebral small vessel disease.

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  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: Netherlands NLM ID: 9432592 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1569-1802 (Electronic) Linking ISSN: 0945053X NLM ISO Abbreviation: Matrix Biol Subsets: MEDLINE
    • Publication Information:
      Publication: Amsterdam : Elsevier
      Original Publication: Stuttgart ; New York : Fischer, c1994-
    • Subject Terms:
      Cerebral Small Vessel Diseases*/genetics ; Cerebral Small Vessel Diseases*/metabolism ; Collagen Type XVIII*/genetics ; Collagen Type XVIII*/metabolism ; Neuroinflammatory Diseases*; Animals ; Humans ; Infant ; Mice ; Endostatins ; Extracellular Matrix/metabolism ; Heparan Sulfate Proteoglycans/metabolism ; Mice, Knockout
    • Abstract:
      Collagen type XVIII (COL18) is an abundant heparan sulfate proteoglycan in vascular basement membranes. Here, we asked (i) if the loss of COL18 would result in blood-brain barrier (BBB) breakdown, pathological alterations of small arteries and capillaries and neuroinflammation as found in cerebral small vessel disease (CSVD) and (ii) if such changes may be associated with remodeling of synapses and neural extracellular matrix (ECM). We found that 5-month-old Col18a1 -/- mice had elevated BBB permeability for mouse IgG in the deep gray matter, and intravascular erythrocyte accumulations were observed brain-wide in capillaries and arterioles. BBB permeability increased with age and affected cortical regions and the hippocampus in 12-month-old Col18a1 -/- mice. None of the Col18a1 -/- mice displayed hallmarks of advanced CSVD, such as hemorrhages, and did not show perivascular space enlargement. Col18a1 deficiency-induced BBB leakage was accompanied by activation of microglia and astrocytes, a loss of aggrecan in the ECM of perineuronal nets associated with fast-spiking inhibitory interneurons and accumulation of the perisynaptic ECM proteoglycan brevican and the microglial complement protein C1q at excitatory synapses. As the pathway underlying these regulations, we found increased signaling through the TGF-ß1/Smad3/TIMP-3 cascade. We verified the pivotal role of COL18 for small vessel wall structure in CSVD by demonstrating the protein's involvement in vascular remodeling in autopsy brains from patients with cerebral hypertensive arteriopathy. Our study highlights an association between the alterations of perivascular ECM, extracellular proteolysis, and perineuronal/perisynaptic ECM, as a possible substrate of synaptic and cognitive alterations in CSVD.
      Competing Interests: Declaration of competing interest The authors declare that they have no competing interests.
      (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
    • Contributed Indexing:
      Keywords: Brevican; Collagen XVIII; Extracellular matrix; Microglia; Neuroinflammation; Small vessel disease; TIMP-3
    • Accession Number:
      0 (Collagen Type XVIII)
      0 (Endostatins)
      0 (Heparan Sulfate Proteoglycans)
      0 (COL18A1 protein, human)
    • Publication Date:
      Date Created: 20240222 Date Completed: 20240401 Latest Revision: 20240403
    • Publication Date:
      20240403
    • Accession Number:
      10.1016/j.matbio.2024.02.007
    • Accession Number:
      38387749