Revascularization of transplanted pancreatic islets following culture with stimulators of angiogenesis.
BACKGROUND
Insufficient revascularization of transplanted islets may result in chronic hypoxia and loss of islet function. This study investigated whether simple culture of islets with angiogenic substances before transplantation could improve graft revascularization.


METHODS
Mouse islets were cultured with vascular endothelial growth factor (VEGF; 20 ng/ml), fibroblast growth factor 2 (FGF-2; 20 ng/ml) or matrix metalloproteinase 9 (MMP-9; 1 mug/ml). Thereafter, 250 islets were implanted beneath the renal capsule of syngeneic C57Bl/6 mice. One month posttransplantation, blood flow (laser-Doppler flowmetry), oxygen tension (Clark microelectrodes), and vascular density were measured and correlated to graft function.


RESULTS
Treatment of islets with VEGF during culture caused islet blood vessels to dilate, whereas FGF-2 treatment induced endothelial cell proliferation. However, the number of capillaries in both cases decreased during culture. When investigated one month posttransplantation, both VEGF and FGF-2 pretreated islets had similar or worse vascular engraftment when compared to transplanted control islets. MMP-9 pretreatment of islets increased vascular density, blood flow and oxygen tension within the grafts. Animals receiving MMP-9 pretreated islets returned, however, more slowly to normoglycemia than control animals, and performed worse than controls in a glucose tolerance test one month posttransplantation.


CONCLUSIONS
Treatment of islets during culture with VEGF or FGF-2 changed the islet vascular phenotype, but capillaries were still lost. Notably, the number of capillaries in the grafted islets one month posttransplantation was in all cases strikingly similar to that observed prior to transplantation. MMP-9 pretreatment of islets elicited an angiogenic response, which improved revascularization of the transplanted islets.
Olsson
Richard
R
Department of Medical Cell Biology, Uppsala University, Sweden. richard.olsson@medcellbiol.uu.se
Maxhuni
Arber
A
Carlsson
Per-Ola
PO
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D007515:Islets of Langerhans / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism / Q000601:surgery; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000378:metabolism; D010186:Pancreatic Function Tests; D013997:Time Factors; D046509:Tissue Culture Techniques; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
D043925:Angiogenesis Inducing Agents; D042461:Vascular Endothelial Growth Factor A; D010100:Oxygen