title: Pericytes are involved in the pathogenesis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.
abstract: OBJECTIVE
  Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common inherited small-vessel disease, is associated with vascular aggregation of mutant Notch3 protein, dysfunction of cerebral vessels, and dementia. Pericytes, perivascular cells involved in microvascular function, express Notch3. Therefore, we hypothesize that these cells may play a role in the pathogenesis of CADASIL.
  
  
  METHODS
  Two-, 7-, and 12-month-old CADASIL mutant mice (TgNotch3(R169C) ) and wild-type controls were examined regarding Notch3 aggregation in pericytes, the coverage of cerebral vessels by pericytes, pericyte numbers, capillary density, blood-brain barrier (BBB) integrity, astrocytic end-feet, and the expression of astrocytic gap junction and endothelial adherens junction protein using immunostaining and Western blot analysis. In addition, we examined cerebrovascular CO2 reactivity using laser Doppler fluxmetry and in vivo microscopy.
  
  
  RESULTS
  With increasing age, mutated Notch3 aggregated around pericytes and smooth muscle cells. Notch3 aggregation caused significant reduction of pericyte number and coverage of capillaries by pericyte processes (p < 0.01). These changes were associated with detachment of astrocytic end-feet from cerebral microvessels, leakage of plasma proteins, reduction in expression of endothelial adherens junction protein, and reduced microvascular reactivity to CO2 . Smooth muscle cells were not affected by Notch3 accumulation.
  
  
  CONCLUSIONS
  Our results show that pericytes are the first cells affected by Notch3 aggregation in CADASIL mice. Pericyte pathology causes opening of the BBB and microvascular dysfunction. Therefore, protecting pericytes may represent a novel therapeutic strategy for vascular dementia.
authors: Institute for Stroke and Dementia Research, University of Munich Medical Center, Ludwig Maximilian University, Munich.|Experimental Neurosurgery, Department of Neurosurgery, Rechts der Isar Hospital, Technical University Munich, Munich.|Munich Cluster for Systems Neurology (SyNergy), Munich.
authors: Mitrajit
authors: M
authors: Ghosh
authors: Institute for Stroke and Dementia Research, University of Munich Medical Center, Ludwig Maximilian University, Munich.|Graduate School of Systemic Neurosciences, Ludwig Maximilian University, Munich.
authors: Matilde
authors: M
authors: Balbi
authors: Institute for Stroke and Dementia Research, University of Munich Medical Center, Ludwig Maximilian University, Munich.|Munich Cluster for Systems Neurology (SyNergy), Munich.
authors: Farida
authors: F
authors: Hellal
authors: Institute for Stroke and Dementia Research, University of Munich Medical Center, Ludwig Maximilian University, Munich.|Munich Cluster for Systems Neurology (SyNergy), Munich.
authors: Martin
authors: M
authors: Dichgans
authors: Experimental Neurosurgery, Department of Neurosurgery, Rechts der Isar Hospital, Technical University Munich, Munich.|Munich Cluster for Systems Neurology (SyNergy), Munich.|Translational Neurosurgery and Neurobiology, Department of Neurosurgery, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors: Ute
authors: U
authors: Lindauer
authors: Institute for Stroke and Dementia Research, University of Munich Medical Center, Ludwig Maximilian University, Munich.|Munich Cluster for Systems Neurology (SyNergy), Munich.
authors: Nikolaus
authors: N
authors: Plesnila
mesh_terms: D000367:Age Factors; D000818:Animals; D001812:Blood-Brain Barrier / Q000473:pathology*; D046589:CADASIL / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002196:Capillaries / Q000473:pathology*; D002540:Cerebral Cortex / Q000098:blood supply*; D004195:Disease Models, Animal; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D020286:Pericytes / Q000378:metabolism / Q000473:pathology*; D011897:Random Allocation; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D016037:Single-Blind Method
chemical_list: C499373:Notch3 protein, mouse; D000071656:Receptor, Notch3; D051880:Receptors, Notch