title: Haploinsufficiency of the insulin-like growth factor-1 receptor enhances endothelial repair and favorably modifies angiogenic progenitor cell phenotype.
abstract: OBJECTIVE
  Defective endothelial regeneration predisposes to adverse arterial remodeling and is thought to contribute to cardiovascular disease in type 2 diabetes mellitus. We recently demonstrated that the type 1 insulin-like growth factor receptor (IGF1R) is a negative regulator of insulin sensitivity and nitric oxide bioavailability. In this report, we examined partial deletion of the IGF1R as a potential strategy to enhance endothelial repair.
  
  
  RESULTS
  We assessed endothelial regeneration after wire injury in mice and abundance and function of angiogenic progenitor cells in mice with haploinsufficiency of the IGF1R (IGF1R(+/-)). Endothelial regeneration after arterial injury was accelerated in IGF1R(+/-) mice. Although the yield of angiogenic progenitor cells was lower in IGF1R(+/-) mice, these angiogenic progenitor cells displayed enhanced adhesion, increased secretion of insulin-like growth factor-1, and enhanced angiogenic capacity. To examine the relevance of IGF1R manipulation to cell-based therapy, we transfused IGF1R(+/-) bone marrow-derived CD117(+) cells into wild-type mice. IGF1R(+/-) cells accelerated endothelial regeneration after arterial injury compared with wild-type cells and did not alter atherosclerotic lesion formation.
  
  
  CONCLUSIONS
  Haploinsufficiency of the IGF1R is associated with accelerated endothelial regeneration in vivo and enhanced tube forming and adhesive potential of angiogenic progenitor cells in vitro. Partial deletion of IGF1R in transfused bone marrow-derived CD117(+) cells enhanced their capacity to promote endothelial regeneration without altering atherosclerosis. Our data suggest that manipulation of the IGF1R could be exploited as novel therapeutic approach to enhance repair of the arterial wall after injury.
authors.affiliation: From the Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, United Kingdom.
authors.forename: Nadira Y
authors.initials: NY
authors.lastname: Yuldasheva
authors.affiliation: From the Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, United Kingdom.
authors.forename: Sheikh Tawqeer
authors.initials: ST
authors.lastname: Rashid
authors.affiliation: From the Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, United Kingdom.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Haywood
authors.affiliation: From the Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Cordell
authors.affiliation: From the Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, United Kingdom.
authors.forename: Romana
authors.initials: R
authors.lastname: Mughal
authors.affiliation: From the Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, United Kingdom.
authors.forename: Hema
authors.initials: H
authors.lastname: Viswambharan
authors.affiliation: From the Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, United Kingdom.
authors.forename: Helen
authors.initials: H
authors.lastname: Imrie
authors.affiliation: From the Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, United Kingdom.
authors.forename: Piruthivi
authors.initials: P
authors.lastname: Sukumar
authors.affiliation: From the Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, United Kingdom.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Cubbon
authors.affiliation: From the Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, United Kingdom.
authors.forename: Amir
authors.initials: A
authors.lastname: Aziz
authors.affiliation: From the Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Gage
authors.affiliation: From the Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, United Kingdom.
authors.forename: Kamatamu Amanda
authors.initials: KA
authors.lastname: Mbonye
authors.affiliation: From the Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, United Kingdom.
authors.forename: Jessica
authors.initials: J
authors.lastname: Smith
authors.affiliation: From the Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, United Kingdom.
authors.forename: Stacey
authors.initials: S
authors.lastname: Galloway
authors.affiliation: From the Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Skromna
authors.affiliation: From the Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, United Kingdom.
authors.forename: D Julian A
authors.initials: DJ
authors.lastname: Scott
authors.affiliation: From the Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, United Kingdom.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Kearney
authors.affiliation: From the Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, United Kingdom. s.b.wheatcroft@leeds.ac.uk.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Wheatcroft
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency; D002340:Carotid Artery Diseases / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D002448:Cell Adhesion; D004730:Endothelium, Vascular / Q000378:metabolism / Q000502:physiology*; D005260:Female; D005263:Femoral Artery / Q000293:injuries*; D005786:Gene Expression Regulation; D005838:Genotype; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012038:Regeneration
chemical_list: D001057:Apolipoproteins E; D012333:RNA, Messenger; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D017526:Receptor, IGF Type 1
keywords: endothelium