Journal
DIABETOLOGIA
Volume 43, Issue 6, Pages 763-772Publisher
SPRINGER VERLAG
DOI: 10.1007/s001250051374
Keywords
diabetes; islet transplantation; angiogenesis; hepatocyte growth factor and c-MET receptor; and urokinase plasminogen activator; bFGF; TGF-beta; TGF-alpha
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Funding
- NIDDK NIH HHS [DK-50657, DK-36836] Funding Source: Medline
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Aims/hypothesis. The vascularisation of newly transplanted islets originates from the recipients. Because islets transplanted into a diabetic do less well than those transplanted into a euglycaemic environment, we examined the hypothesis that gene expression of angiogenic factors in grafts is delayed in diabetes. These factors include hepatocyte growth factor (HGF) and its receptor c-MET, and urokinase plasminogen activator (uPA) and its receptor uPAR, basic fibroblast growth factor (bFGF), TGF-alpha and TGF beta-1. Methods. Isolated rat islets were studied in vitro under normoxic and hypoxic culture conditions and gene expression was determined with semi-quantitative multiplex RT-PCR. We found that HGF but not c-MET expression was induced by hypoxia in vitro. Using syngeneic Lewis rats, gene expression was also studied in grafts on days 1, 3, 5, 7 and 14 after transplantation. Results. In grafts of normoglycaemic rats, HGF expression was enhanced on day 3 and maintained whereas expression of c-MET fell and remained down until day 14. Expression of uPA was up at day 3 and remained high; expression of uPAR was also up at day 3 but then fell to control levels at day 14. Expression of bFGF, TGF-alpha and TGF beta-1 persisted throughout. Vimentin, a marker of fibroblasts, had increased expression at day 1 which was further enhanced in subsequent days. In the grafts of diabetic recipients the expression of HGF, uPA and uPAR were delayed, being clearly expressed at day 5 rather than day 3. Vimentin expression was similarly delayed. Conclusion/interpretation. This apparent delay in angiogenesis provides a potential mechanism for the less favourable outcomes of islets transplanted into diabetic recipients.
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