Severity of arterial defects in the retina correlates with the burden of intracerebral haemorrhage in COL4A1-related stroke
| Autor: | Emmanuelle Plaisier, Nicolas Mezouar, Ambre Rochey, Anne Joutel, Julien Ratelade, Valérie Domenga-Denier |
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| Přispěvatelé: | Génétique et Physiopathologie des Maladies Cérébro-Vasculaires (U1161 / UMR_S 1161), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Des Maladies Rénales Rares aux Maladies Fréquentes, Remodelage et Réparation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), DHU NeuroVasc Sorbonne Paris-Cité, Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Dupuis, Christine |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
MESH: Cerebral Hemorrhage Pathology Time Factors [SDV]Life Sciences [q-bio] Penetrance Degeneration (medical) MESH: Mice Knockout Muscle Smooth Vascular MESH: Blood-Brain Barrier chemistry.chemical_compound 0302 clinical medicine MESH: Penetrance MESH: Animals MESH: Endothelial Cells MESH: Peptide Fragments Stroke Mice Knockout MESH: Genetic Predisposition to Disease intracerebral haemorrhage MESH: Myocytes Smooth Muscle MESH: Muscle Smooth Vascular 3. Good health [SDV] Life Sciences [q-bio] medicine.anatomical_structure Blood-Brain Barrier retinal imaging Disease Progression MESH: Disease Progression Collagen Type IV medicine.medical_specialty Mice 129 Strain Retinal Artery COL4A1 Myocytes Smooth Muscle COL4A2 MESH: Stroke Pathology and Forensic Medicine 03 medical and health sciences MESH: Mice 129 Strain MESH: Mice Inbred C57BL MESH: Cell Proliferation Parenchyma medicine Animals Genetic Predisposition to Disease Pathological MESH: Collagen Type IV smooth muscle cell Cell Proliferation Cerebral Hemorrhage Basement membrane Retina MESH: Retinal Artery business.industry MESH: Time Factors Endothelial Cells Retinal medicine.disease basement membrane Peptide Fragments Mice Inbred C57BL Disease Models Animal 030104 developmental biology chemistry MESH: Disease Models Animal business 030217 neurology & neurosurgery |
| Zdroj: | The Journal of Pathology The Journal of pathology and bacteriology The Journal of pathology and bacteriology, John Wiley & Sons, 2018, 244 (4), pp.408-420. ⟨10.1002/path.5023⟩ |
| ISSN: | 0022-3417 0368-3494 1555-2039 |
| DOI: | 10.1002/path.5023 |
| Popis: | International audience; Mutations in the α1 (COL4A1) or α2 (COL4A2) chains of collagen type IV, a major component of the vascular basement membrane, cause intracerebral haemorrhages with variable expressivity and reduced penetrance by mechanisms that remain poorly understood. Here we sought to investigate the cellular mechanisms of COL4A1-related intracerebral haemorrhage and identify a marker for haemorrhage risk stratification. A combination of histological, immunohistochemical, and electron microscopy analyses were used to analyse the brain parenchyma, cerebrovasculature, and retinal vessels of mice expressing the disease-causing COL4A1 p.G498V mutation. Mutant mice developed cerebral microhaemorrhages and macroscopic haemorrhages (macrohaemorrhages), the latter with reduced penetrance, mimicking the human disease. Microhaemorrhages that occurred in early postnatal life were associated with a transient, generalized increase in blood-brain barrier permeability at the level of capillaries. Macrohaemorrhages, which occurred later in life, originated from deep brain arteries with focal loss of smooth muscle cells. Similar smooth muscle cell loss was detected in retinal arteries, and a time-course analysis of arterial lesions showed that smooth muscle cells are recruited normally in arterial wall during development, but undergo progressive apoptosis-mediated degeneration. By assessing in parallel the extent of these retinal arterial lesions and the presence/absence of macrohaemorrhages, we found that the arterial lesion load in the retina is strongly correlated with the burden of macrohaemorrhages. We conclude that microhaemorrhages and macrohaemorrhages are driven by two distinct mechanisms. Moreover, smooth muscle cell degeneration is a critical factor underlying the partial penetrance of COL4A1-related macrohaemorrhages, and retinal imaging is a promising tool for identifying high-risk patients. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
| Databáze: | OpenAIRE |
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