title: Improvement of rat islet viability during transplantation: validation of pharmacological approach to induce VEGF overexpression.
abstract: Delayed and insufficient revascularization during islet transplantation deprives islets of oxygen and nutrients, resulting in graft failure. Vascular endothelial growth factor (VEGF) could play a critical role in islet revascularization. We aimed to develop pharmacological strategies  for VEGF overexpression in pancreatic islets using the iron chelator deferoxamine (DFO), thus avoiding obstacles or safety risks associated with gene therapy. Rat pancreatic islets were infected in vivo using an adenovirus (ADE) encoding human VEGF gene (4.10(8) pfu/pancreas) or were  incubated in the presence of DFO (10 μmol/L). In vitro viability, functionality, and the secretion of VEGF were evaluated in islets 1 and 3 days after treatment. Infected islets or islets incubated with DFO were transplanted into the liver of syngenic diabetic rats and the graft efficiency  was estimated in vivo by measuring body weight, glycemia, C-peptide secretion, and animal survival over a period of 2 months. DFO induced transient VEGF overexpression over 3 days, whereas infection with ADE resulted in prolonged VEGF overexpression lasting 14 days; however, this was toxic  and decreased islet viability and functionality. The in vivo study showed a decrease in rat deaths after the transplantation of islets treated with DFO or ADE compared with the sham and control group. ADE treatment improved body weight and C-peptide levels. Gene therapy and DFO improved metabolic  control in diabetic rats after transplantation, but this effect was limited in the presence of DFO. The pharmacological approach is an interesting strategy for improving graft efficiency during transplantation, but this approach needs to be improved with drugs that are more specific.
authors.affiliation: Centre Européen d'étude du Diabète, Strasbourg, France. a.langlois@ceed-diabete.org
authors.forename: A
authors.initials: A
authors.lastname: Langlois
authors.forename: W
authors.initials: W
authors.lastname: Bietiger
authors.forename: E
authors.initials: E
authors.lastname: Seyfritz
authors.forename: E
authors.initials: E
authors.lastname: Maillard
authors.forename: K
authors.initials: K
authors.lastname: Vivot
authors.forename: C
authors.initials: C
authors.lastname: Peronet
authors.forename: N
authors.initials: N
authors.lastname: Meyer
authors.forename: L
authors.initials: L
authors.lastname: Kessler
authors.forename: N
authors.initials: N
authors.lastname: Jeandidier
authors.forename: M
authors.initials: M
authors.lastname: Pinget
authors.forename: S
authors.initials: S
authors.lastname: Sigrist
mesh_terms: D000257:Adenoviridae Infections / Q000473:pathology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003676:Deferoxamine / Q000494:pharmacology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology / Q000821:virology; D016381:Islets of Langerhans Transplantation; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D015203:Reproducibility of Results; D014022:Tissue Survival / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D042461:Vascular Endothelial Growth Factor A; D003676:Deferoxamine