Author + information
- Received April 29, 2019
- Revision received July 15, 2019
- Accepted July 16, 2019
- Published online December 23, 2019.
- Darcy Lidington, PhDa,b,∗,
- Jessica C. Fares, MSca,b,∗,
- Franziska E. Uhl, PhDc,
- Danny D. Dinh, MSca,b,
- Jeffrey T. Kroetsch, PhDa,b,
- Meghan Sauvé, PhDa,b,
- Firhan A. Malik, PhDa,
- Frank Matthes, PhDc,
- Lotte Vanherle, MScc,
- Arman Adel, BSca,
- Abdul Momen, MD, PhDd,
- Hangjun Zhang, MDa,b,
- Roozbeh Aschar-Sobbi, PhDe,
- Warren D. Foltz, PhDf,
- Hoyee Wan, BScg,h,i,
- Manabu Sumiyoshi, MDh,j,
- R. Loch Macdonald, MD, PhDg,h,
- Mansoor Husain, MDa,d,k,l,
- Peter H. Backx, PhD, DVMe,m,
- Scott P. Heximer, PhDa,k,
- Anja Meissner, PhDa,c,† and
- Steffen-Sebastian Bolz, MD, PhDa,b,k,†∗ ()
- aDepartment of Physiology, University of Toronto, Toronto, Ontario, Canada
- bToronto Centre for Microvascular Medicine at The Ted Rogers Centre for Heart Research Translational Biology and Engineering Program, University of Toronto, Ontario, Canada
- cWallenberg Center for Molecular Medicine and Department of Experimental Medical Science, Lund University, Lund, Sweden
- dDivision of Cell & Molecular Biology, Toronto General Hospital Research Institute, Toronto, Ontario, Canada
- eDivision of Cardiology, University Health Network, Toronto, Ontario, Canada
- fSTTARR Innovation Centre, Department of Radiation Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada
- gLabatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada
- hDivision of Neurosurgery, St. Michael’s Hospital, and Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- iSunnybrook Research Institute, Physical Sciences Platform and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- jInstitute of Health Biosciences, Department of Neurosurgery, University of Tokushima Graduate School, Tokushima, Japan
- kHeart & Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research, University of Toronto, Toronto, Ontario, Canada
- lDepartment of Medicine, University of Toronto, Toronto, Ontario, Canada
- mDepartment of Biology, York University, Toronto, Ontario, Canada
- ↵∗Address for correspondence:
Dr. Steffen-Sebastian Bolz, Toronto Centre for Microvascular Medicine at TBEP, University of Toronto, 661 University Avenue, 14th Floor, Toronto, Ontario, Canada, M5G 1M1.
• The cystic fibrosis transmembrane conductance regulator (CFTR) is a significant modulator of cerebrovascular reactivity; the loss of CFTR function enhances myogenic vasoconstriction.
• Heart failure and subarachnoid hemorrhage downregulate cerebrovascular CFTR protein expression; this leads to enhanced cerebral artery vasoconstriction, reduced cerebral perfusion, neuronal injury, and ultimately, neurologic deficits.
• CFTR therapeutics that maintain CFTR expression normalize the perfusion deficits, reduce neuronal injury, and improve neurologic function in these pathological settings.
Heart failure (HF) and subarachnoid hemorrhage (SAH) chronically reduce cerebral perfusion, which negatively affects clinical outcome. This work demonstrates a strong relationship between cerebral artery cystic fibrosis transmembrane conductance regulator (CFTR) expression and altered cerebrovascular reactivity in HF and SAH. In HF and SAH, CFTR corrector compounds (C18 or lumacaftor) normalize pathological alterations in cerebral artery CFTR expression, vascular reactivity, and cerebral perfusion, without affecting systemic hemodynamic parameters. This normalization correlates with reduced neuronal injury. Therefore, CFTR therapeutics have emerged as valuable clinical tools to manage cerebrovascular dysfunction, impaired cerebral perfusion, and neuronal injury.
- cognitive impairment
- corrector compounds
- cystic fibrosis transmembrane conductance regulator (CFTR)
- myogenic vasoconstriction
- tumor necrosis factor
- vascular smooth muscle cells
↵∗ Dr. Lidington and Ms. Fares contributed equally to this work and are joint first authors.
↵† Drs. Meissner and Bolz contributed equally to this work and are joint senior authors.
Dr. Kroetsch was supported by a Queen Elizabeth II/Heart & Stroke Foundation of Ontario Graduate Scholarship in Science and Technology. Dr. Sauvé was supported by Canadian Institutes of Health Research (CIHR) Doctoral Research Award and by Natural Sciences and Engineering Research Council (NSERC) of Canada. Dr. Dinh was supported by a NSERC MATCH scholarship. Dr. Malik was supported by a PGS-D doctoral scholarship. Dr. Backx was supported by the Canadian Institutes of Health Research (CIHR) (PJT 153159). Dr. Heximer was supported by CIHR (MOP-106670). Dr. Meissner was supported by the Swedish Science Council (VR 2017-01243), the Åke Wibergs Stiftelse (M17-0031), the Knut & Alice Wallenberg Foundation (2015.0030), and Lund University. Dr. Bolz was supported by the Operating and Infrastructure Grants from the Heart and Stroke Foundation of Ontario (HFSO) (G13-0002610 and G16-00014175) and CIHR (PJT 153269); a HSFO Career Investigator Award (CI-7432) and Mid-Career Investigator Award; the Brain Aneurysm Foundation (Northwell Health - North Shore University Hospital Brain Aneurysm Centre Chair of Research Award); the Canadian Foundation for Innovation and Ontario Research Fund (11810); and research support from the University of Toronto. Dr. Macdonald is chief scientific officer of Edge Therapeutics, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received April 29, 2019.
- Revision received July 15, 2019.
- Accepted July 16, 2019.
- 2019 The Authors