title: Diabetes-Induced Jagged1 Overexpression in Endothelial Cells Causes Retinal Capillary Regression in a Murine Model of Diabetes Mellitus: Insights Into Diabetic Retinopathy.
abstract: Several mechanisms have been proposed to account for diabetes-induced microvasculopathy (DMV). Although Notch signaling was reported to be affected by glucose metabolism in endothelial cells during developmental angiogenesis, it has not been investigated in vascular remodeling of adult capillaries in relation to diabetes mellitus.
  
  
  
  We induced diabetes mellitus in 8-week-old adult mice by intravenously administering streptozotocin. After 6 weeks, we harvested organs, including retina, heart, and skeletal muscle, and evaluated the capillaries with immunofluorescence and confocal microscopy. We modulated endothelial Notch signaling using chemical inhibitors in wild-type mice or transgenic mice, inducing conditional knockout of Jagged1 or Mib1.
  
  
  
  DMV was characterized by capillary remodeling, regression, and decreased density. Notch ligand Jagged1, but not δ-like ligand 4, was markedly increased in endothelial cells of diabetic mice. Using endothelium-specific Jagged1 knockdown mice, we found that blocking Jagged1 prevented DMV even under diabetic conditions. Furthermore, in the inducible endothelium-specific Jagged1 knockdown mice, blocking Jagged1 even at 4 weeks after the establishment of DMV could reverse it, leading to normalization of retinal vasculature. A search for downstream signals revealed that diabetes mellitus decreased the nuclear localization of Notch1 intracellular domain and reduced the expression of VE-cadherin and N-cadherin in endothelial cells. Chemical Notch inhibition phenocopied DMV in normal mice.
  
  
  
  Our findings indicate that diabetes mellitus induces Jagged1 overexpression and suppresses Notch signaling in endothelial cells, leading to DMV in adult mice. We conclude that dysregulated intercellular Notch signaling may be a novel mechanism of DMV.
authors.affiliation: From the Cardiovascular Center and Department of Internal Medicine (C.-H.Y., Y.R.C., I.-H.C.) and Department of Ophthalmology (S.J.W.), Seoul National University Bundang Hospital, Seongnam, South Korea; Department of Biomedical Sciences, Seoul National University Graduate School, South Korea (Y.-E.C., J.-i.C., H.-S.K.); Molecular Medicine & Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, South Korea (S.-J.K., T.-W.K., H.-S.K.); and Innovative Research Institute for Cell Therapy, Seoul National University Hospital, South Korea (Y.-B.P., H.-S.K.).
authors.forename: Chang-Hwan
authors.initials: CH
authors.lastname: Yoon
authors.affiliation: From the Cardiovascular Center and Department of Internal Medicine (C.-H.Y., Y.R.C., I.-H.C.) and Department of Ophthalmology (S.J.W.), Seoul National University Bundang Hospital, Seongnam, South Korea; Department of Biomedical Sciences, Seoul National University Graduate School, South Korea (Y.-E.C., J.-i.C., H.-S.K.); Molecular Medicine & Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, South Korea (S.-J.K., T.-W.K., H.-S.K.); and Innovative Research Institute for Cell Therapy, Seoul National University Hospital, South Korea (Y.-B.P., H.-S.K.).
authors.forename: Young-Eun
authors.initials: YE
authors.lastname: Choi
authors.affiliation: From the Cardiovascular Center and Department of Internal Medicine (C.-H.Y., Y.R.C., I.-H.C.) and Department of Ophthalmology (S.J.W.), Seoul National University Bundang Hospital, Seongnam, South Korea; Department of Biomedical Sciences, Seoul National University Graduate School, South Korea (Y.-E.C., J.-i.C., H.-S.K.); Molecular Medicine & Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, South Korea (S.-J.K., T.-W.K., H.-S.K.); and Innovative Research Institute for Cell Therapy, Seoul National University Hospital, South Korea (Y.-B.P., H.-S.K.).
authors.forename: Young Ryun
authors.initials: YR
authors.lastname: Cha
authors.affiliation: From the Cardiovascular Center and Department of Internal Medicine (C.-H.Y., Y.R.C., I.-H.C.) and Department of Ophthalmology (S.J.W.), Seoul National University Bundang Hospital, Seongnam, South Korea; Department of Biomedical Sciences, Seoul National University Graduate School, South Korea (Y.-E.C., J.-i.C., H.-S.K.); Molecular Medicine & Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, South Korea (S.-J.K., T.-W.K., H.-S.K.); and Innovative Research Institute for Cell Therapy, Seoul National University Hospital, South Korea (Y.-B.P., H.-S.K.).
authors.forename: Seok-Jin
authors.initials: SJ
authors.lastname: Koh
authors.affiliation: From the Cardiovascular Center and Department of Internal Medicine (C.-H.Y., Y.R.C., I.-H.C.) and Department of Ophthalmology (S.J.W.), Seoul National University Bundang Hospital, Seongnam, South Korea; Department of Biomedical Sciences, Seoul National University Graduate School, South Korea (Y.-E.C., J.-i.C., H.-S.K.); Molecular Medicine & Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, South Korea (S.-J.K., T.-W.K., H.-S.K.); and Innovative Research Institute for Cell Therapy, Seoul National University Hospital, South Korea (Y.-B.P., H.-S.K.).
authors.forename: Jae-Il
authors.initials: JI
authors.lastname: Choi
authors.affiliation: From the Cardiovascular Center and Department of Internal Medicine (C.-H.Y., Y.R.C., I.-H.C.) and Department of Ophthalmology (S.J.W.), Seoul National University Bundang Hospital, Seongnam, South Korea; Department of Biomedical Sciences, Seoul National University Graduate School, South Korea (Y.-E.C., J.-i.C., H.-S.K.); Molecular Medicine & Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, South Korea (S.-J.K., T.-W.K., H.-S.K.); and Innovative Research Institute for Cell Therapy, Seoul National University Hospital, South Korea (Y.-B.P., H.-S.K.).
authors.forename: Tae-Won
authors.initials: TW
authors.lastname: Kim
authors.affiliation: From the Cardiovascular Center and Department of Internal Medicine (C.-H.Y., Y.R.C., I.-H.C.) and Department of Ophthalmology (S.J.W.), Seoul National University Bundang Hospital, Seongnam, South Korea; Department of Biomedical Sciences, Seoul National University Graduate School, South Korea (Y.-E.C., J.-i.C., H.-S.K.); Molecular Medicine & Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, South Korea (S.-J.K., T.-W.K., H.-S.K.); and Innovative Research Institute for Cell Therapy, Seoul National University Hospital, South Korea (Y.-B.P., H.-S.K.).
authors.forename: Se Joon
authors.initials: SJ
authors.lastname: Woo
authors.affiliation: From the Cardiovascular Center and Department of Internal Medicine (C.-H.Y., Y.R.C., I.-H.C.) and Department of Ophthalmology (S.J.W.), Seoul National University Bundang Hospital, Seongnam, South Korea; Department of Biomedical Sciences, Seoul National University Graduate School, South Korea (Y.-E.C., J.-i.C., H.-S.K.); Molecular Medicine & Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, South Korea (S.-J.K., T.-W.K., H.-S.K.); and Innovative Research Institute for Cell Therapy, Seoul National University Hospital, South Korea (Y.-B.P., H.-S.K.).
authors.forename: Young-Bae
authors.initials: YB
authors.lastname: Park
authors.affiliation: From the Cardiovascular Center and Department of Internal Medicine (C.-H.Y., Y.R.C., I.-H.C.) and Department of Ophthalmology (S.J.W.), Seoul National University Bundang Hospital, Seongnam, South Korea; Department of Biomedical Sciences, Seoul National University Graduate School, South Korea (Y.-E.C., J.-i.C., H.-S.K.); Molecular Medicine & Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, South Korea (S.-J.K., T.-W.K., H.-S.K.); and Innovative Research Institute for Cell Therapy, Seoul National University Hospital, South Korea (Y.-B.P., H.-S.K.). hyosoo@snu.ac.kr usahyosoo@gmail.com ihchae@snu.ac.kr.
authors.forename: In-Ho
authors.initials: IH
authors.lastname: Chae
authors.affiliation: From the Cardiovascular Center and Department of Internal Medicine (C.-H.Y., Y.R.C., I.-H.C.) and Department of Ophthalmology (S.J.W.), Seoul National University Bundang Hospital, Seongnam, South Korea; Department of Biomedical Sciences, Seoul National University Graduate School, South Korea (Y.-E.C., J.-i.C., H.-S.K.); Molecular Medicine & Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, South Korea (S.-J.K., T.-W.K., H.-S.K.); and Innovative Research Institute for Cell Therapy, Seoul National University Hospital, South Korea (Y.-B.P., H.-S.K.). hyosoo@snu.ac.kr usahyosoo@gmail.com ihchae@snu.ac.kr.
authors.forename: Hyo-Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis; D002196:Capillaries / Q000473:pathology; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D003930:Diabetic Retinopathy / Q000378:metabolism* / Q000517:prevention & control; D003984:Dibenzazepines / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D000072100:Jagged-1 Protein / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D042787:Receptor, TIE-2 / Q000235:genetics; D051880:Receptors, Notch / Q000502:physiology; D012171:Retinal Vessels / Q000473:pathology*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency
chemical_list: D003984:Dibenzazepines; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D051880:Receptors, Notch; C470629:MIB1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; C527817:dibenzazepine
keywords: capillaries; diabetes complications; diabetes mellitus; intercellular signaling peptides and proteins; pathologic angiogenesis