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.
Article and author information
Author details
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.
Metrics
-
- 1,900
- views
-
- 431
- downloads
-
- 59
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
Further reading
-
- Neuroscience
Chronic pain is a prevalent and debilitating condition whose neural mechanisms are incompletely understood. An imbalance of cerebral excitation and inhibition (E/I), particularly in the medial prefrontal cortex (mPFC), is believed to represent a crucial mechanism in the development and maintenance of chronic pain. Thus, identifying a non-invasive, scalable marker of E/I could provide valuable insights into the neural mechanisms of chronic pain and aid in developing clinically useful biomarkers. Recently, the aperiodic component of the electroencephalography (EEG) power spectrum has been proposed to represent a non-invasive proxy for E/I. We, therefore, assessed the aperiodic component in the mPFC of resting-state EEG recordings in 149 people with chronic pain and 115 healthy participants. We found robust evidence against differences in the aperiodic component in the mPFC between people with chronic pain and healthy participants, and no correlation between the aperiodic component and pain intensity. These findings were consistent across different subtypes of chronic pain and were similarly found in a whole-brain analysis. Their robustness was supported by preregistration and multiverse analyses across many different methodological choices. Together, our results suggest that the EEG aperiodic component does not differentiate between people with chronic pain and healthy individuals. These findings and the rigorous methodological approach can guide future studies investigating non-invasive, scalable markers of cerebral dysfunction in people with chronic pain and beyond.
-
- Neuroscience
Recent studies suggest that calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN) represent aversive information and signal a general alarm to the forebrain. If CGRP neurons serve as a true general alarm, their activation would modulate both passive nad active defensive behaviors depending on the magnitude and context of the threat. However, most prior research has focused on the role of CGRP neurons in passive freezing responses, with limited exploration of their involvement in active defensive behaviors. To address this, we examined the role of CGRP neurons in active defensive behavior using a predator-like robot programmed to chase mice. Our electrophysiological results revealed that CGRP neurons encode the intensity of aversive stimuli through variations in firing durations and amplitudes. Optogenetic activation of CGRP neuron during robot chasing elevated flight responses in both conditioning and retention tests, presumably by amyplifying the perception of the threat as more imminent and dangerous. In contrast, animals with inactivated CGRP neurons exhibited reduced flight responses, even when the robot was programmed to appear highly threatening during conditioning. These findings expand the understanding of CGRP neurons in the PBN as a critical alarm system, capable of dynamically regulating active defensive behaviors by amplifying threat perception, ensuring adaptive responses to varying levels of danger.
