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@ARTICLE{Kraft:139442,
      author       = {Kraft, Peter and Schuhmann, Michael K and Garz, Cornelia
                      and Jandke, Solveig and Urlaub, Daniela and Mencl, Stine and
                      Zernecke, Alma and Heinze, Hans-Jochen and Carare, Roxana O
                      and Kleinschnitz, Christoph and Schreiber, Stefanie},
      title        = {{H}ypercholesterolemia induced cerebral small vessel
                      disease.},
      journal      = {PLOS ONE},
      volume       = {12},
      number       = {8},
      issn         = {1932-6203},
      address      = {San Francisco, California, US},
      publisher    = {PLOS},
      reportid     = {DZNE-2020-05764},
      pages        = {e0182822},
      year         = {2017},
      abstract     = {BackgroundWhile hypercholesterolemia plays a causative role
                      for the development of ischemic stroke in large vessels, its
                      significance for cerebral small vessel disease (CSVD)
                      remains unclear. We thus aimed to understand the detailed
                      relationship between hypercholesterolemia and CSVD using the
                      well described Ldlr-/- mouse model.MethodsWe used Ldlr-/-
                      mice (n = 16) and wild-type (WT) mice (n = 15) at the age of
                      6 and 12 months. Ldlr-/- mice develop high plasma
                      cholesterol levels following a high fat diet. We analyzed
                      cerebral capillaries and arterioles for intravascular
                      erythrocyte accumulations, thrombotic vessel occlusions,
                      blood-brain barrier (BBB) dysfunction and
                      microbleeds.ResultsWe found a significant increase in the
                      number of erythrocyte stases in 6 months old Ldlr-/- mice
                      compared to all other groups (P < 0.05). Ldlr-/- animals
                      aged 12 months showed the highest number of thrombotic
                      occlusions while in WT animals hardly any occlusions could
                      be observed (P < 0.001). Compared to WT mice, Ldlr-/- mice
                      did not display significant gray matter BBB breakdown.
                      Microhemorrhages were observed in one Ldlr-/- mouse that was
                      6 months old. Results did not differ when considering
                      subcortical and cortical regions.ConclusionsIn Ldlr-/- mice,
                      hypercholesterolemia is related to a thrombotic CSVD
                      phenotype, which is different from hypertension-related CSVD
                      that associates with a hemorrhagic CSVD phenotype. Our data
                      demonstrate a relationship between hypercholesterolemia and
                      the development of CSVD. Ldlr-/- mice appear to be an
                      adequate animal model for research into CSVD.},
      keywords     = {Animals / Blood-Brain Barrier: physiopathology / Brain:
                      physiopathology / Cerebral Small Vessel Diseases: blood /
                      Cerebral Small Vessel Diseases: etiology / Cerebral Small
                      Vessel Diseases: genetics / Cerebral Small Vessel Diseases:
                      physiopathology / Cholesterol: blood / Diet, High-Fat /
                      Disease Models, Animal / Hypercholesterolemia: blood /
                      Hypercholesterolemia: complications / Hypercholesterolemia:
                      genetics / Hypercholesterolemia: physiopathology / Male /
                      Mice / Mice, Knockout / Receptors, LDL: genetics /
                      Receptors, LDL (NLM Chemicals) / Cholesterol (NLM
                      Chemicals)},
      cin          = {AG Reymann / U Clinical Researchers - Magdeburg},
      ddc          = {610},
      cid          = {I:(DE-2719)1310005 / I:(DE-2719)7000000},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342) / 344
                      - Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-342 / G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:28796818},
      pmc          = {pmc:PMC5552130},
      doi          = {10.1371/journal.pone.0182822},
      url          = {https://pub.dzne.de/record/139442},
}