Mechanistic insights into a TIMP3-sensitive pathway constitutively engaged in the regulation of cerebral hemodynamics
- INSERM, France
- University of Vermont, United States
- Institute of Biochemistry, Medical Faculty, Christian Albrechts University, Germany
- University of Vermont, University of Manchester, United States
Abstract
Cerebral small vessel disease (SVD) is a leading cause of stroke and dementia. CADASIL, an inherited SVD, alters cerebral artery function, compromising blood flow to the working brain. TIMP3 (tissue inhibitor of metalloproteinase 3) accumulation in the vascular extracellular matrix in CADASIL is a key contributor to cerebrovascular dysfunction. However, the linkage between elevated TIMP3 and compromised cerebral blood flow (CBF) remains unknown. Here, we show that TIMP3 acts through inhibition of the metalloprotease ADAM17 and HB-EGF to regulate cerebral arterial tone and blood flow responses. In a clinically relevant CADASIL mouse model, we show that exogenous ADAM17 or HB-EGF restores cerebral arterial tone and blood flow responses, and identify upregulated voltage-dependent potassium channel (KV) number in cerebral arterial myocytes as a heretofore-unrecognized downstream effector of TIMP3-induced deficits. These results support the concept that the balance of TIMP3 and ADAM17 activity modulates CBF through regulation of myocyte KV channel number.
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Funding
Agence Nationale de la Recherche (ANR Genopath 2009-RAE09011HSA and ANR Blanc 2010-RPV11011HHA)
- Anne Joutel
Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain)
- Mark T Nelson
- Anne Joutel
European Union (Horizon 2020 research and innovation programme SVDs@target, grant agreement No 666881)
- Mark T Nelson
- Anne Joutel
National Institute of Health (R37DK053832, PO1HL095488, RO1HL44455, R01HL121706, R01HL131181)
- Mark T Nelson
Totman Medical Research Trust
- Mark T Nelson
United Leukodystrophy Foundation (CADASIL Research Grant)
- Fabrice Dabertrand
Deutsche Forschungsgemeinschaft (DFG, SFB877 project A1 and the Cluster of Excellence Inflammation at Interfaces)
- Athena Chalaris
- Stefan Rose-John
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments were conducted in full accordance with the French guidelines for the use of animals in research and were approved by the "Lariboisière-Villemin" Institutional Animal Care and Use Committee (C2EA 09), with every effort made to minimize the number of animals used.
Copyright
© 2016, Capone et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Mechanistic insights into a TIMP3-sensitive pathway constitutively engaged in the regulation of cerebral hemodynamics
eLife 5:e17536.
https://doi.org/10.7554/eLife.17536
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