Collagen IV deficiency causes hypertrophic remodeling and endothelium-dependent hyperpolarization in small vessel disease with intracerebral hemorrhageResearch in context
Sarah McNeilly,
Cameron R. Thomson,
Laura Gonzalez-Trueba,
Yuan Yan Sin,
Alessandra Granata,
Graham Hamilton,
Michelle Lee,
Erin Boland,
John D. McClure,
Cristina Lumbreras-Perales,
Alisha Aman,
Apoorva A. Kumar,
Marco Cantini,
Caglar Gök,
Delyth Graham,
Yasuko Tomono,
Christopher D. Anderson,
Yinhui Lu,
Colin Smith,
Hugh S. Markus,
Marc Abramowicz,
Catheline Vilain,
Rustam Al-Shahi Salman,
Manuel Salmeron-Sanchez,
Atticus H. Hainsworth,
William Fuller,
Karl E. Kadler,
Neil J. Bulleid,
Tom Van Agtmael
Affiliations
Sarah McNeilly
School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
Cameron R. Thomson
School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
Laura Gonzalez-Trueba
School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
Yuan Yan Sin
School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
Alessandra Granata
Department of Clinical Neurosciences, Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge and Royal Papworth Hospital, Cambridge, UK
Graham Hamilton
School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK; Glasgow Polyomics, University of Glasgow, Glasgow, UK
Michelle Lee
School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
Erin Boland
School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
John D. McClure
School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
Cristina Lumbreras-Perales
School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
Alisha Aman
School of Health and Wellbeing, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
Apoorva A. Kumar
Molecular and Clinical Sciences Research Institute, St George’s University of London, London, UK; Princess Royal University Hospital, Kings College Hospital NHS Foundation Trust, London, UK
Marco Cantini
Centre for the Cellular Microenvironment, School of Science and Engineering, University of Glasgow, Glasgow, UK
Caglar Gök
School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
Delyth Graham
School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
Yasuko Tomono
Division of Molecular & Cell Biology, Shigei Medical Research Institute, Okayama, Japan
Christopher D. Anderson
Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
Yinhui Lu
Wellcome Centre for Cell Matrix Research, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, UK
Colin Smith
Academic Neuropathology, University of Edinburgh, Edinburgh, UK
Hugh S. Markus
Department of Neurology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
Marc Abramowicz
Department of Genetics, Hôpital Erasme, ULB Center of Human Genetics, Universite Libre de Bruxelles, Bruxelles, Belgium
Catheline Vilain
Department of Genetics, Hôpital Erasme, ULB Center of Human Genetics, Universite Libre de Bruxelles, Bruxelles, Belgium
Rustam Al-Shahi Salman
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
Manuel Salmeron-Sanchez
Centre for the Cellular Microenvironment, School of Science and Engineering, University of Glasgow, Glasgow, UK
Atticus H. Hainsworth
Molecular and Clinical Sciences Research Institute, St George’s University of London, London, UK
William Fuller
School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
Karl E. Kadler
Wellcome Centre for Cell Matrix Research, Faculty of Biology, Medicine & Health, University of Manchester, Manchester, UK
Neil J. Bulleid
School of Molecular Biosciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
Tom Van Agtmael
School of Cardiovascular and Metabolic Health, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK; Corresponding author.
Summary: Background: Genetic variants in COL4A1 and COL4A2 (encoding collagen IV alpha chain 1/2) occur in genetic and sporadic forms of cerebral small vessel disease (CSVD), a leading cause of stroke, dementia and intracerebral haemorrhage (ICH). However, the molecular mechanisms of CSVD with ICH and COL4A1/COL4A2 variants remain obscure. Methods: Vascular function and molecular investigations in mice with a Col4a1 missense mutation and heterozygous Col4a2 knock-out mice were combined with analysis of human brain endothelial cells harboring COL4A1/COL4A2 mutations, and brain tissue of patients with sporadic CSVD with ICH. Findings: Col4a1 missense mutations cause early-onset CSVD independent of hypertension, with enhanced vasodilation of small arteries due to endothelial dysfunction, vascular wall thickening and reduced stiffness. Mechanistically, the early-onset dysregulated endothelium-dependent hyperpolarization (EDH) is due to reduced collagen IV levels with elevated activity and levels of endothelial Ca2+-sensitive K+ channels. This results in vasodilation via the Na/K pump in vascular smooth muscle cells. Our data support this endothelial dysfunction preceding development of CSVD-associated ICH is due to increased cytoplasmic Ca2+ levels in endothelial cells. Moreover, cerebral blood vessels of patients with sporadic CSVD show genotype-dependent mechanisms with wall thickening and lower collagen IV levels in those harboring common non-coding COL4A1/COL4A2 risk alleles. Interpretation: COL4A1/COL4A2 variants act in genetic and sporadic CSVD with ICH via dysregulated EDH, and altered vascular wall thickness and biomechanics due to lower collagen IV levels and/or mutant collagen IV secretion. These data highlight EDH and collagen IV levels as potential treatment targets. Funding: MRC, Wellcome Trust, BHF.
