1. Reducing Hypermuscularization of the Transitional Segment Between Arterioles and Capillaries Protects Against Spontaneous Intracerebral Hemorrhage
- Author
-
Monara Kaelle Servulo Cruz Angelim, Nicholas R. Klug, Julien Ratelade, Mark T. Nelson, Valérie Domenga-Denier, Fabrice Dabertrand, Anne Joutel, Damiano Lombardi, Rustam Al-Shahi Salman, Colin Smith, Jean-Frédéric Gerbeau, Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University of Vermont [Burlington], COmputational Mathematics for bio-MEDIcal Applications (COMMEDIA), Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jacques-Louis Lions (LJLL (UMR_7598)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), University of Colorado Anschutz [Aurora], University of Edinburgh, Inria Siège, Institut National de Recherche en Informatique et en Automatique (Inria), University of Manchester [Manchester], Université Sorbonne Paris Cité (USPC), This work was supported by Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain) to AJ and MTN, the European Union (Horizon 2020 Research and Innovation Programme SVDs@target under the grant agreement n° 666881), the French National Agency of Research (ANR I-Can) and the French Fondation for Rare Diseases to AJ, the National Institute of Neurological Disorders and Stroke (NINDS) and National Institute of Aging (NIA) (R01NS110656), the National Institutes of Health under Award Number R35HL140027 and the Henry M. Jackson Foundation for the Advancement of Military Medicine (HU0001-18-2-0016) to MTN. The LINCHPIN study was funded by UK Medical Research Council (MRC) and The Stroke Association. The Edinburgh Brain Bank, part of the MRC UK Brain Bank Network, curates the brain tissue from LINCHPIN study tissue donors and controls who died suddenly from non-neurological conditions. The Edinburgh Brain Bank is funded by both MRC and The Stroke Association., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Martinez Rico, Clara, Institute of Psychiatry and Neurosciences of Paris, INSERM U1266, University of Paris, Paris, France., Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT., Inria Paris, Sorbonne University, Laboratory Jacques-Louis Lions, Paris, France, Institute of Psychiatry and Neurosciences of Paris, INSERM U1266, University of Paris, Paris, France, Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT, Department of Anesthesiology, Department of Pharmacology, Anschutz Medical Campus, University of Colorado, Aurora, CO, Institute of Psychiatry and Neurosciences of Paris, INSERM U1266, University of Paris, Paris, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK, Division of Cardiovascular Sciences, University of Manchester, Manchester, UK, DHU NeuroVasc, Sorbonne Paris Cité, Paris, France., Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm - Paris Descartes), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Pathology ,[SDV]Life Sciences [q-bio] ,Gene Expression ,Retinal Neovascularization ,Hypermuscularization ,Muscle, Smooth, Vascular ,Mice ,0302 clinical medicine ,Transitional segment ,Receptor, Notch3 ,Mice, Knockout ,Collagen IV ,0303 health sciences ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Hyperplasia ,Immunohistochemistry ,Molecular Imaging ,3. Good health ,[SDV] Life Sciences [q-bio] ,medicine.anatomical_structure ,cardiovascular system ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Disease Susceptibility ,Cardiology and Cardiovascular Medicine ,Collagen Type IV ,medicine.medical_specialty ,Genotype ,Myocytes, Smooth Muscle ,Retina ,Article ,Mural cell ,Contractility ,03 medical and health sciences ,Downregulation and upregulation ,Arteriole ,Physiology (medical) ,medicine.artery ,Genetic model ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,medicine ,Animals ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,cardiovascular diseases ,Cerebral Hemorrhage ,030304 developmental biology ,Intracerebral hemorrhage ,business.industry ,Notch3 ,medicine.disease ,Disease Models, Animal ,Microvessels ,Mutation ,business ,Biomarkers ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,030217 neurology & neurosurgery - Abstract
Background: Spontaneous deep intracerebral hemorrhage (ICH) is a devastating subtype of stroke without specific treatments. It has been thought that smooth muscle cell (SMC) degeneration at the site of arteriolar wall rupture may be sufficient to cause hemorrhage. However, deep ICHs are rare in some aggressive small vessel diseases that are characterized by significant arteriolar SMC degeneration. Here we hypothesized that a second cellular defect may be required for the occurrence of ICH. Methods: We studied a genetic model of spontaneous deep ICH using Col4a1 +/G498V and Col4a1 +/G1064D mouse lines that are mutated for the α1 chain of collagen type IV. We analyzed cerebroretinal microvessels, performed genetic rescue experiments, vascular reactivity analysis, and computational modeling. We examined postmortem brain tissues from patients with sporadic deep ICH. Results: We identified in the normal cerebroretinal vasculature a novel segment between arterioles and capillaries, herein called the transitional segment (TS), which is covered by mural cells distinct from SMCs and pericytes. In Col4a1 mutant mice, this TS was hypermuscularized, with a hyperplasia of mural cells expressing more contractile proteins, whereas the upstream arteriole exhibited a loss of SMCs. TSs mechanistically showed a transient increase in proliferation of mural cells during postnatal maturation. Mutant brain microvessels, unlike mutant arteries, displayed a significant upregulation of SM genes and Notch3 target genes, and genetic reduction of Notch3 in Col4a1 +/G498V mice protected against ICH. Retina analysis showed that hypermuscularization of the TS was attenuated, but arteriolar SMC loss was unchanged in Col4a1 +/G498V , Notch3 +/− mice. Moreover, hypermuscularization of the retinal TS increased its contractility and tone and raised the intravascular pressure in the upstream feeding arteriole. We similarly found hypermuscularization of the TS and focal arteriolar SMC loss in brain tissues from patients with sporadic deep ICH. Conclusions: Our results suggest that hypermuscularization of the TS, through increased Notch3 activity, is involved in the occurrence of ICH in Col4a1 mutant mice, by raising the intravascular pressure in the upstream feeding arteriole and promoting its rupture at the site of SMC loss. Our human data indicate that these 2 mutually reinforcing vascular defects may represent a general mechanism of deep ICH.
- Published
- 2020
- Full Text
- View/download PDF