title: Notch3 is necessary for blood vessel integrity in the central nervous system.
abstract: 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.
  
  
  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.
authors.affiliation: 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.).
authors.forename: Tanya L
authors.initials: TL
authors.lastname: Henshall
authors.affiliation: 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.).
authors.forename: Annika
authors.initials: A
authors.lastname: Keller
authors.affiliation: 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.).
authors.forename: Liqun
authors.initials: L
authors.lastname: He
authors.affiliation: 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.).
authors.forename: Bengt R
authors.initials: BR
authors.lastname: Johansson
authors.affiliation: 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.).
authors.forename: Elisabet
authors.initials: E
authors.lastname: Wallgard
authors.affiliation: 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.).
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Raschperger
authors.affiliation: 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.).
authors.forename: Maarja Andaloussi
authors.initials: MA
authors.lastname: Mäe
authors.affiliation: 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.).
authors.forename: Shaobo
authors.initials: S
authors.lastname: Jin
authors.affiliation: 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.). Christer.Betsholtz@igp.uu.se Urban.Lendahl@ki.se.
authors.forename: Christer
authors.initials: C
authors.lastname: Betsholtz
authors.affiliation: 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.). Christer.Betsholtz@igp.uu.se Urban.Lendahl@ki.se.
authors.forename: Urban
authors.initials: U
authors.lastname: Lendahl
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D001808:Blood Vessels / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D002199:Capillary Permeability; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055806:Microvessels / Q000378:metabolism / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D020286:Pericytes / Q000378:metabolism; D010641:Phenotype; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012171:Retinal Vessels / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D015415:Biomarkers; C499373:Notch3 protein, mouse; D000071656:Receptor, Notch3; D051880:Receptors, Notch
keywords: Notch3; aneurysm; blood-brain barrier; fibrin; smooth muscle