title: High glucose-induced jagged 1 in endothelial cells disturbs notch signaling for angiogenesis: a novel mechanism of diabetic vasculopathy.
abstract: Angiogenesis is a multistep process which is orchestrated by intercellular signaling. We developed an in vitro model of human angiogenesis to identify a pathologic angiogenesis and intercellular signaling in high glucose condition. We co-cultivated human endothelial cells (ECs) and smooth muscle cells (SMCs) in a spheroid on an SMC monolayer for 7 days either in high glucose or in control condition. We analyzed vascular growth and expression of notch or its ligands with confocal microscopy. Abnormal angiogenesis by high glucose condition was characterized by (1) increased sprouting and branching (high glucose vs. normal: number of sprouts 20.3±1.5 vs. 13.7±2.9, p=0.024; number of branching points 7.6±2.5 vs. 2.3±2.1, p=0.047), (2) decreased vascular diameter (diameter of the tubes 13.4±6. 1μm vs. 19.1±8.8 μm, p=0.012) and (3) destabilization of the tubes. We identified that high glucose induced jagged 1 and suppressed notch1 in ECs whereas it did not affect Dll4. Constitutive jagged 1 overexpression or inhibition of notch1 in ECs induced abnormal angiogenesis as the high glucose condition did. Endothelial-specific shRNA targeting jagged 1 rescued the aberrant angiogenesis in high glucose condition. High glucose condition induced an abnormal endothelial intercellular signaling leading to aberrant angiogenesis. It is a novel mechanism of diabetic microvasculopathy which can be a therapeutic target beyond glucose control.
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University Hospital, Seoul, Republic of Korea; Cardiovascular Center & Department of Internal Medicine, Seoul National University Bundang Hospital, Republic of Korea.
authors.forename: Chang-Hwan
authors.initials: CH
authors.lastname: Yoon
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Young-Eun
authors.initials: YE
authors.lastname: Choi
authors.affiliation: Molecular Medicine & Biopharmaceutical Sciences, WCU Program, Seoul National University, Seoul, Republic of Korea.
authors.forename: Seok-Jin
authors.initials: SJ
authors.lastname: Koh
authors.affiliation: Molecular Medicine & Biopharmaceutical Sciences, WCU Program, Seoul National University, Seoul, Republic of Korea.
authors.forename: Jae-Il
authors.initials: JI
authors.lastname: Choi
authors.affiliation: Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Young-Bae
authors.initials: YB
authors.lastname: Park
authors.affiliation: National Research Laboratory for Stem Cell Niche, Seoul National University Hospital, Seoul, Republic of Korea; Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Republic of Korea; Molecular Medicine & Biopharmaceutical Sciences, WCU Program, Seoul National University, Seoul, Republic of Korea. Electronic address: hyosoo@snu.ac.kr.
authors.forename: Hyo-Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003925:Diabetic Angiopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D013549:Sweetening Agents / Q000494:pharmacology
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D013549:Sweetening Agents; D005947:Glucose
keywords: Angiogenesis; Cell signaling; Diabetes mellitus; Endothelium; Vascular complications