title: The role of Notch signaling in diabetic endothelial progenitor cells dysfunction.
abstract: OBJECTIVE
  To investigate the role of Notch signaling pathway in vasculogenic dysfunction of diabetic EPCs (DM-EPCs).
  
  
  METHODS
  The study was performed in mice and diabetes was induced with Streptozotocin. The functional consequences of Notch pathway modulation were studied by assessment of colony forming capacity (EPC colony forming assay), EPC differentiation capacity (% of definitive EPC-CFU (dEPC-CFU)), circulating EPCs (EPC culture assay) and migrated cells (migration assay); in the presence of Notch inhibitor (γ-secretase inhibitors (GSI)) compared to control. Notch pathway and VEGF involvement in DM- EPCs were assessed by gene expression (RT-qPCR).
  
  
  RESULTS
  DM demonstrated to increase Notch pathway expression in bone marrow (BM) EPCs followed by lower EPC-CFU number, EPCs differentiation capacity, number of circulating EPCs, migrated cells and VEGF expression compared to control (p<0.05). Inhibition of Notch pathway by GSI rescued vasculogenic dysfunction in DM-EPCs as represented by increase in EPC-CFU number, differentiation capacity and number of circulating EPCs (p<0.05).
  
  
  CONCLUSIONS
  Our findings indicate the involvement of Notch pathway in mediating DM-EPCs dysfunction including less number of EPC-CFU, circulating EPCs and migrated cell number compared to control. Further in vitro inhibition of Notch pathway by GSI rescued DM-EPC dysfunction. Therefore targeting Notch pathway in DM may provide a target to restore DM-EPC dysfunction.
authors.affiliation: Department of Plastic Reconstructive Surgery, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan; Department of Cardiovascular Medicine, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan; Department of Histology, Faculty of Medicine, Universitas Indonesia, Jakarta, Jalan Salemba Raya No. 6 Jakarta Pusat, 10430, Indonesia. Electronic address: ds_histoui@outlook.com.
authors.forename: Dewi
authors.initials: D
authors.lastname: Sukmawati
authors.affiliation: Department of Plastic Reconstructive Surgery, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan. Electronic address: rtanaka@juntendo.ac.jp.
authors.forename: Rica
authors.initials: R
authors.lastname: Tanaka
authors.affiliation: Department of Plastic Reconstructive Surgery, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan. Electronic address: rhirano@juntendo.ac.jp.
authors.forename: Rie
authors.initials: R
authors.lastname: Ito-Hirano
authors.affiliation: Department of Plastic Reconstructive Surgery, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan. Electronic address: sfujimu@juntendo.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fujimura
authors.affiliation: Department of Plastic Reconstructive Surgery, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan. Electronic address: ayhayashi@juntendo.ac.jp.
authors.forename: Ayato
authors.initials: A
authors.lastname: Hayashi
authors.affiliation: Department of Cardiovascular Medicine, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan. Electronic address: iseigo@juntendo.ac.jp.
authors.forename: Seigo
authors.initials: S
authors.lastname: Itoh
authors.affiliation: Department of Plastic Reconstructive Surgery, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan. Electronic address: hmizuno@juntendo.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mizuno
authors.affiliation: Department of Cardiovascular Medicine, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan. Electronic address: daida@juntendo.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Daida
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001773:Blood Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003925:Diabetic Angiopathies / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D066026:Endothelial Progenitor Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D011480:Protease Inhibitors / Q000494:pharmacology; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013047:Specific Pathogen-Free Organisms; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: C497762:Notch1 protein, mouse; D011480:Protease Inhibitors; D051881:Receptor, Notch1; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; D053829:Amyloid Precursor Protein Secretases
keywords: Diabetes; Endothelial progenitor cells; Notch signaling pathway; Vasculogenesis; γ-Secretase inhibitor