title: Insulin resistance impairs circulating angiogenic progenitor cell function and delays endothelial regeneration.
abstract: OBJECTIVE
  Circulating angiogenic progenitor cells (APCs) participate in endothelial repair after arterial injury. Type 2 diabetes is associated with fewer circulating APCs, APC dysfunction, and impaired endothelial repair. We set out to determine whether insulin resistance adversely affects APCs and endothelial regeneration.
  
  
  METHODS
  We quantified APCs and assessed APC mobilization and function in mice hemizygous for knockout of the insulin receptor (IRKO) and wild-type (WT) littermate controls. Endothelial regeneration after femoral artery wire injury was also quantified after APC transfusion.
  
  
  RESULTS
  IRKO mice, although glucose tolerant, had fewer circulating Sca-1(+)/Flk-1(+) APCs than WT mice. Culture of mononuclear cells demonstrated that IRKO mice had fewer APCs in peripheral blood, but not in bone marrow or spleen, suggestive of a mobilization defect. Defective vascular endothelial growth factor-stimulated APC mobilization was confirmed in IRKO mice, consistent with reduced endothelial nitric oxide synthase (eNOS) expression in bone marrow and impaired vascular eNOS activity. Paracrine angiogenic activity of APCs from IRKO mice was impaired compared with those from WT animals. Endothelial regeneration of the femoral artery after denuding wire injury was delayed in IRKO mice compared with WT. Transfusion of mononuclear cells from WT mice normalized the impaired endothelial regeneration in IRKO mice. Transfusion of c-kit(+) bone marrow cells from WT mice also restored endothelial regeneration in IRKO mice. However, transfusion of c-kit(+) cells from IRKO mice was less effective at improving endothelial repair.
  
  
  CONCLUSIONS
  Insulin resistance impairs APC function and delays endothelial regeneration after arterial injury. These findings support the hypothesis that insulin resistance per se is sufficient to jeopardize endogenous vascular repair. Defective endothelial repair may be normalized by transfusion of APCs from insulin-sensitive animals but not from insulin-resistant animals.
authors.affiliation: Division of Cardiovascular and Diabetes Research, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds, UK.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Kahn
authors.forename: Nadira Y
authors.initials: NY
authors.lastname: Yuldasheva
authors.forename: Richard M
authors.initials: RM
authors.lastname: Cubbon
authors.forename: Jessica
authors.initials: J
authors.lastname: Smith
authors.forename: Sheikh T
authors.initials: ST
authors.lastname: Rashid
authors.forename: Hema
authors.initials: H
authors.lastname: Viswambharan
authors.forename: Helen
authors.initials: H
authors.lastname: Imrie
authors.forename: Afroze
authors.initials: A
authors.lastname: Abbas
authors.forename: Adil
authors.initials: A
authors.lastname: Rajwani
authors.forename: Amir
authors.initials: A
authors.lastname: Aziz
authors.forename: Vivek
authors.initials: V
authors.lastname: Baliga
authors.forename: Piruthivi
authors.initials: P
authors.lastname: Sukumar
authors.forename: Matthew
authors.initials: M
authors.lastname: Gage
authors.forename: Mark T
authors.initials: MT
authors.lastname: Kearney
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Wheatcroft
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D005838:Genotype; D007333:Insulin Resistance / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: D052250:Nitric Oxide Synthase Type III; D011972:Receptor, Insulin