title: Reducing Timp3 or vitronectin ameliorates disease manifestations in CADASIL mice.
abstract: OBJECTIVE
  CADASIL is a genetic paradigm of cerebral small vessel disease caused by NOTCH3 mutations that stereotypically lead to the extracellular deposition of NOTCH3 ectodomain (Notch3(ECD) ) on the vessels. TIMP3 and vitronectin are 2 extracellular matrix proteins that abnormally accumulate in Notch3(ECD) -containing deposits on brain vessels of mice and patients with CADASIL. Herein, we investigated whether increased levels of TIMP3 and vitronectin are responsible for aspects of CADASIL disease phenotypes.
  
  
  METHODS
  Timp3 and vitronectin expression were genetically reduced in TgNotch3(R169C) mice, a well-established preclinical model of CADASIL. A mouse overexpressing human TIMP3 (TgBAC-TIMP3) was developed. Disease-related phenotypes, including cerebral blood flow (CBF) deficits, white matter lesions, and Notch3(ECD) deposition, were evaluated between 6 and 20 months of age.
  
  
  RESULTS
  CBF responses to neural activity (functional hyperemia), topical application of vasodilators, and decreases in blood pressure (CBF autoregulation) were similarly reduced in TgNotch3(R169C) and TgBAC-TIMP3 mice, and myogenic responses of brain arteries were likewise attenuated. These defects were rescued in TgNotch3(R169C) mice by haploinsufficiency of Timp3, although the number of white matter lesions was unaffected. In contrast, haploinsufficiency or loss of vitronectin in TgNotch3(R169C) mice ameliorated white matter lesions, although CBF responses were unchanged. Amelioration of cerebrovascular reactivity or white matter lesions in these mice was not associated with reduced Notch3(ECD) deposition in brain vessels.
  
  
  CONCLUSIONS
  Elevated levels of TIMP3 and vitronectin, acting downstream of Notch3(ECD) deposition, play a role in CADASIL, producing divergent influences on early CBF deficits and later white matter lesions.
authors.affiliation: Genetics and Pathogenesis of Cerebrovascular Diseases, Inserm, U1161 and Univ Paris Diderot, Sorbonne Paris Cité, UMRS 1161, F-75010, Paris, France.|DHU NeuroVasc, Sorbonne Paris Cité, Paris, France.
authors.forename: Carmen
authors.initials: C
authors.lastname: Capone
authors.affiliation: Genetics and Pathogenesis of Cerebrovascular Diseases, Inserm, U1161 and Univ Paris Diderot, Sorbonne Paris Cité, UMRS 1161, F-75010, Paris, France.|DHU NeuroVasc, Sorbonne Paris Cité, Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Cognat
authors.affiliation: Genetics and Pathogenesis of Cerebrovascular Diseases, Inserm, U1161 and Univ Paris Diderot, Sorbonne Paris Cité, UMRS 1161, F-75010, Paris, France.|DHU NeuroVasc, Sorbonne Paris Cité, Paris, France.
authors.forename: Lamia
authors.initials: L
authors.lastname: Ghezali
authors.affiliation: Genetics and Pathogenesis of Cerebrovascular Diseases, Inserm, U1161 and Univ Paris Diderot, Sorbonne Paris Cité, UMRS 1161, F-75010, Paris, France.|DHU NeuroVasc, Sorbonne Paris Cité, Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Baron-Menguy
authors.affiliation: Genetics and Pathogenesis of Cerebrovascular Diseases, Inserm, U1161 and Univ Paris Diderot, Sorbonne Paris Cité, UMRS 1161, F-75010, Paris, France.|DHU NeuroVasc, Sorbonne Paris Cité, Paris, France.
authors.forename: Déborah
authors.initials: D
authors.lastname: Aubin
authors.affiliation: Rare and Common Kidney Diseases, Matrix Remodeling and Tissue Repair, Inserm U1155 and Pierre and Marie Curie University, Sorbonne Universities UMR-S 1155, F-75020, Paris, France.|Department of Emergency Nephrological and Renal Transplantation, Tenon Hospital, AP-HP, F-75020, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Mesnard
authors.affiliation: Institute of Human Genetics, University of Regensburg, Regensburg, Germany.
authors.forename: Heidi
authors.initials: H
authors.lastname: Stöhr
authors.affiliation: Genetics and Pathogenesis of Cerebrovascular Diseases, Inserm, U1161 and Univ Paris Diderot, Sorbonne Paris Cité, UMRS 1161, F-75010, Paris, France.|DHU NeuroVasc, Sorbonne Paris Cité, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Domenga-Denier
authors.affiliation: Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT.|Institute of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Nelson
authors.affiliation: Genetics and Pathogenesis of Cerebrovascular Diseases, Inserm, U1161 and Univ Paris Diderot, Sorbonne Paris Cité, UMRS 1161, F-75010, Paris, France.|DHU NeuroVasc, Sorbonne Paris Cité, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Joutel
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D046589:CADASIL / Q000473:pathology* / Q000503:physiopathology*; D002560:Cerebrovascular Circulation; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*; D019096:Vitronectin / Q000378:metabolism*; D000097792:Tissue Inhibitor of Metalloproteinase-4
chemical_list: D019714:Tissue Inhibitor of Metalloproteinases; D019096:Vitronectin; D000097792:Tissue Inhibitor of Metalloproteinase-4