Capone, Carmen and Cognat, Emmanuel and Ghezali, Lamia and Baron-Menguy, Celine and Aubin, Deborah and Mesnard, Laurent and Stoehr, Heidi and Domenga-Denier, Valerie and Nelson, Mark T. and Joutel, Anne (2016) Reducing Timp3 or Vitronectin Ameliorates Disease Manifestations in CADASIL Mice. ANNALS OF NEUROLOGY, 79 (3). pp. 387-403. ISSN 0364-5134, 1531-8249
Full text not available from this repository. (Request a copy)Abstract
Objective: CADASIL is a genetic paradigm of cerebral small vessel disease caused by NOTCH3 mutations that stereo-typically lead to the extracellular deposition of NOTCH3 ectodomain (Notch(3ECD)) 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. Interpretation: 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SMALL VESSEL DISEASE; ANGIOTENSIN-II; CAPILLARY PERICYTES; BLOOD-FLOW; NOTCH3; HYPERTENSION; PATHOGENESIS; DYSFUNCTION; PROTEIN; BRAIN; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Humangenetik |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 11 Mar 2019 15:04 |
| Last Modified: | 11 Mar 2019 15:04 |
| URI: | https://pred.uni-regensburg.de/id/eprint/2324 |
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