Tanya L Henshall1, Annika Keller1, Liqun He1, Bengt R Johansson1, Elisabet Wallgard1, Elisabeth Raschperger1, Maarja Andaloussi Mäe1, Shaobo Jin1, Christer Betsholtz2, Urban Lendahl2. 1. 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.). 2. 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.
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. 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.
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.
Authors: Laura B Payne; Huaning Zhao; Carissa C James; Jordan Darden; David McGuire; Sarah Taylor; James W Smyth; John C Chappell Journal: Microcirculation Date: 2019-05-27 Impact factor: 2.628
Authors: Alaina M Reagan; Xiaowu Gu; Sijalu Paudel; Nicole M Ashpole; Michelle Zalles; William E Sonntag; Zoltan Ungvari; Anna Csiszar; Laura Otalora; Willard M Freeman; Michael B Stout; Michael H Elliott Journal: Neurobiol Aging Date: 2018-07-10 Impact factor: 4.673
Authors: Koji Ando; Weili Wang; Di Peng; Ayano Chiba; Anne K Lagendijk; Lindsey Barske; J Gage Crump; Didier Y R Stainier; Urban Lendahl; Katarzyna Koltowska; Benjamin M Hogan; Shigetomo Fukuhara; Naoki Mochizuki; Christer Betsholtz Journal: Development Date: 2019-01-25 Impact factor: 6.868