Elevated vascular endothelial growth factor production in islets improves islet graft vascularization.
Successful islet transplantation depends on the infusion of sufficiently large quantities of islets, of which only approximately 30% become stably engrafted. Rapid and adequate revascularization of transplanted islets is important for islet survival and function. Delayed and insufficient revascularization can deprive islets of oxygen and nutrients, resulting in islet cell death and early graft failure. To improve islet revascularization, we delivered human vascular endothelial growth factor (VEGF) cDNA to murine islets, followed by transplantation under the renal capsule in diabetic mice. Diabetic animals receiving a marginal mass of 300 islets that were pretransduced with a VEGF vector exhibited near normoglycemia. In contrast, diabetic mice receiving an equivalent number of islets that were transduced with a control vector remained hyperglycemic. Immunohistochemistry with anti-insulin and anti-CD31 antibodies revealed a relatively higher insulin content and greater degree of microvasculature in the VEGF vector-transduced islet grafts, which correlated with significantly improved blood glucose profiles and enhanced insulin secretion in response to glucose challenge in this group of diabetic recipient mice. These results demonstrate that VEGF production in islets stimulates graft angiogenesis and enhances islet revascularization. This mechanism might be explored as a novel strategy to accelerate islet revascularization and improve long-term survival of functional islet mass posttransplantation.
Zhang
Nan
N
Carl Icahn Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
Richter
Anja
A
Suriawinata
Jenny
J
Harbaran
Sonal
S
Altomonte
Jennifer
J
Cong
Lin
L
Zhang
Haojiang
H
Song
Keying
K
Meseck
Marcia
M
Bromberg
Jonathan
J
Dong
Hengjiang
H
D000256:Adenoviridae; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000601:surgery*; D004195:Disease Models, Animal; D005822:Genetic Vectors; D006801:Humans; D007515:Islets of Langerhans / Q000098:blood supply*; D016381:Islets of Langerhans Transplantation / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011994:Recombinant Proteins / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*
D001786:Blood Glucose; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A