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Notch3 Is Necessary for Blood Vessel Integrity in the Central Nervous System

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Notch3 Is Necessary for Blood Vessel Integrity in the Central Nervous System Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2015 Notch3 Is Necessary for Blood Vessel Integrity in the Central Nervous System Henshall, T L ; Keller, A ; He, L ; Johansson, B R ; Wallgard, E ; Raschperger, E ; Mae, M A ; Jin, S ; Betsholtz, C ; Lendahl, U DOI: https://doi.org/10.1161/ATVBAHA.114.304849 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-120552 Journal Article Published Version Originally published at: Henshall, T L; Keller, A; He, L; Johansson, B R; Wallgard, E; Raschperger, E; Mae, M A; Jin, S; Betsholtz, C; Lendahl, U (2015). Notch3 Is Necessary for Blood Vessel Integrity in the Central Nervous System. Arteriosclerosis, Thrombosis, and Vascular Biology, 35(2):409-420. DOI: https://doi.org/10.1161/ATVBAHA.114.304849 Notch3 Is Necessary for Blood Vessel Integrity in the Central Nervous System Tanya L. Henshall,* Annika Keller,* Liqun He, Bengt R. Johansson, Elisabet Wallgard, Elisabeth Raschperger, Maarja Andaloussi Mäe, Shaobo Jin, Christer Betsholtz,† Urban Lendahl† Objective—Vascular smooth muscle cells (VSMC) are important for contraction, blood flow distribution, and regulation of blood vessel diameter, but to what extent they contribute to the integrity of blood vessels and blood–brain barrier function is less well understood. In this report, we explored the impact of the loss of VSMC in the Notch3−/− mouse on blood vessel integrity in the central nervous system. Approach and Results—Notch3−/− mice showed focal disruptions of the blood–brain barrier demonstrated by extravasation of tracers accompanied by fibrin deposition in the retinal vasculature. This blood–brain barrier leakage was accompanied by a regionalized and patchy loss of VSMC, with VSMC gaps predominantly in arterial resistance vessels of larger caliber. The loss of VSMC appeared to be caused by progressive degeneration of VSMC resulting in a gradual loss of VSMC marker expression and a progressive acquisition of an aberrant VSMC phenotype closer to the gaps, followed by enhanced apoptosis and cellular disintegration in the gaps. Arterial VSMC were the only mural cell type that was morphologically affected, despite Notch3 also being expressed in pericytes. Transcriptome analysis of isolated brain microvessels revealed gene expression changes in Notch3−/− mice consistent with loss of arterial VSMC and presumably secondary transcriptional changes were observed in endothelial genes, which may explain the compromised vascular integrity. Conclusions—We demonstrate that Notch3 is important for survival of VSMC, and reveal a critical role for Notch3 and VSMC in blood vessel integrity and blood–brain barrier function in the mammalian vasculature. (Arterioscler Thromb Vasc Biol. 2015;35:409-420. DOI: 10.1161/ATVBAHA.114.304849.) Key Words: aneurysm ◼ blood-brain barrier ◼ fibrin ◼ Notch3 ◼ smooth muscle ll blood vessels are composed of 2 principal cell types, what extent the mural cells of larger vessels are also critical Aendothelial cells and mural cells (vascular smooth mus- for the integrity of the BBB is unknown. In this study, we have cle cells [VSMC] and pericytes). Mural cells have different used Notch3−/− mice to address this question, as these mice phenotypic and functional characteristics, depending on the show progressive loss of arterial VSMC over time.5–7 type of blood vessel. For example, VSMC in certain types Notch signaling is an evolutionarily conserved cell–cell sig- of arteries are important regulators of vessel tone and diam- naling mechanism based on interactions between transmem- eter, while in large caliber vessels, VSMC contribute critical brane Notch receptors and Delta/Jagged ligands on juxtaposed extracellular matrix components.1 The function of capillary cells. Signaling ensues when a ligand on the signal-sending pericytes, however, is just beginning to emerge.2 A role for cell interacts with a Notch receptor on the neighboring signal- pericytes at the blood–brain barrier (BBB) was recently dem- receiving cell. Ligand-receptor interaction leads to proteolytic onstrated through analysis of mice mutated in the genes, Pdgfb processing of the Notch receptor, which ultimately releases and Pdgfrb, encoding platelet-derived growth factor-B and the intracellular portion of the receptor (Notch intracellular its receptor, PDGF-B and PDGFR-β, respectively.3,4 In these domain). The Notch intracellular domain then translocates to mice, loss of pericytes led to increased endothelial transcyto- the cell nucleus, where it interacts with the DNA-binding pro- sis and a significant transport of blood-borne tracers, includ- tein, CSL (Cp-binding factor 1 [CBF-1]/recombination signal ing large proteins, across the normally restrictive BBB.3,4 To sequence-binding protein-Jκ [RBP-Jκ], suppressor of hairless Received on: March 24, 2014; final version accepted on: November 13, 2014. From the Department of Cell and Molecular Biology (T.H., S.J., U.L.) and Department of Medical Biochemistry and Biophysics, Division of Vascular Biology (C.B., E.R.), Karolinska Institute, Stockholm, Sweden; Department of Immunology, Genetics, and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden (A.K., L.H., E.R., M.A.M., C.B.); EM Unit, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden (B.R.J.); and Octapharma AB, Stockholm, Sweden (E.W.). *These authors contributed equally to this article. †Shared senior authors. Current address for A.K.: Division of Neurosurgery, University Hospital Zürich, Zürich, Switzerland. The online-only Data Supplement is available with this article at http://atvb.ahajournals.org/lookup/suppl/doi:10.1161/ATVBAHA.114.304849/-/DC1. Correspondence to Professor Christer Betsholtz, Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Uppsala University, 751 85 Uppsala, Sweden. E-mail [email protected]; or Professor Urban Lendahl, Department of Cell and Molecular Biology, Karolinska Institute, SE-171 77 Stockholm, Sweden. E-mail [email protected] © 2014 American Heart Association, Inc. Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.114.304849 Downloaded from http://atvb.ahajournals.org/409 at Universitaet Zuerich on February 5, 2016 410 Arterioscler Thromb Vasc Biol February 2015 Nonstandard Abbreviations and Acronyms Results Gaps in SMA Staining in Notch3−/− Mice β-gal β-galactosidase Correlate With Vessel Type and Size BBB blood–brain barrier To gain better insights into the Notch3−/− vascular phenotype, CADASIL cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy we first wanted to establish whether VSMC alterations in adult −/− CNS central nervous system Notch3 mice were confined to vessels of a specific type and GOM granular osmiophilic material size. To address this, we searched for mural cell phenotypes in the retina of adult Notch3−/− mice, a structure with a highly PDGF-B platelet-derived growth factor-B visible vascular tree: primary arterioles radiate out of the SMA α-smooth muscle actin optic nerve head and stretch across the retinal inner surface TEM transmission electron microscopy while undergoing progressive branching. We found patchy VSMC vascular smooth muscle cells loss of expression of α-smooth muscle actin (SMA; a VSMC marker) along retinal arterioles leaving apparent gaps in the SMA-positive VSMC coat adjacent to regions with sparse [Su(h)], and Lag-1) and induces transcription of downstream and irregular SMA staining (Figure 1A), in agreement with target genes.8 previously published work.7 Extensive loss of SMA staining Notch signaling plays a pivotal role during vascular develop- was observed along the Notch3−/− primary radial arterioles ment. Genetic targeting of several Notch pathway components (Figure 1B; boxed area), and the SMA loss was then quan- in endothelial cells (Notch1, Dll4, RBP-Jκ) leads to severe tified along the proximodistal arterial axis of these vessels. defects in angiogenic sprouting and vessel remodeling.9,10 The When scoring arterioles in the central (0–820 μm), middle Notch3 receptor is closely related to Notch1, 2, and 411,12 and (820–1640 μm), and peripheral (1640–2710 μm) portions of is expressed in VSMC. Upregulation of human NOTCH3 as the retina (Figure 1C), SMA loss was predominantly observed a consequence of hypoxia is observed in VSMC in pulmo- in the central and middle regions, whereas the distal region nary arterial hypertension, and reduction of Notch3 signaling was largely preserved (Figure 1D). The arteriolar branching mitigates pathogenesis of pulmonary arterial hypertension in pattern showed no significant difference between the differ- mice.13 Mutations in the NOTCH3 gene are the cause of cere- ent genotypes (Figure I in the online-only Data Supplement), bral autosomal dominant arteriopathy with subcortical infarcts in agreement with a recent report.7 Loss of VSMC coverage and leukoencephalopathy (CADASIL),14 the most common appeared specific to arterioles, as we could not detect simi- inherited stroke and dementia syndrome in the group of degen- lar changes in venules (Figure II in the online-only Data erative small vessel diseases.15 In patients with CADASIL, Supplement). VSMC degenerate over time and an electron-dense extracel- In the adult Notch3−/− mouse, SMA gaps were also lular material, granular osmiophilic material (GOM) is depos- observed in brain arteries (Figure III in the online-only
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