In vivo non-viral gene delivery of human vascular endothelial growth factor improves revascularisation and restoration of euglycaemia after human islet transplantation into mouse liver

Diabetologia. 2010 Aug;53(8):1669-79. doi: 10.1007/s00125-010-1745-5. Epub 2010 Apr 20.

Abstract

Aims/hypothesis: Delivery of the gene for human vascular endothelial growth factor (VEGF, also known as VEGFA) to both the transplanted islets and the surrounding tissue may promote islet revascularisation and survival. We previously showed the effective delivery of VEGF gene to rat myocardium by an ultrasound-mediated gene-transfer method named ultrasound-targeted microbubble destruction (UTMD). Here we examined the effect of non-viral VEGF delivery using UTMD on transplanted islets in vivo.

Methods: A marginal number of human islets were transplanted into livers of mice which were a model for diabetes. Then, non-viral plasmid vectors encoding VEGF (VEGF group, n = 11) or the gene for green fluorescent protein (GFP) (GFP group, n = 7) were introduced into the host liver by UTMD. Transplantation without gene delivery was performed as a control (no-UTMD group, n = 8). Blood glucose, serum human insulin, C-peptide levels and the revascularisation in graft islets were evaluated.

Results: Restoration of euglycaemia occurred in 13% in the no-UTMD group and 14% in the GFP group, whereas 73% mice in the VEGF group became euglycaemic at day 30 (p < 0.05 in no-UTMD vs VEGF). Serum human insulin and C-peptide were significantly higher in the VEGF group at day 32 (insulin: no-UTMD, 17 +/- 8; GFP, 37 +/- 17; VEGF, 109 +/- 26 pmol/l, respectively, p < 0.05; C-peptide: no-UTMD, 68 +/- 38; GFP, 115 +/- 58; VEGF, 791 +/- 230 pmol/l, respectively, p < 0.05). Vessel density in graft islets was significantly higher in the VEGF group (no-UTMD, 169 +/- 36; GFP, 227 +/- 39; VEGF, 649 +/- 51 counts/mm(2), respectively, p < 0.05).

Conclusions/interpretation: Delivery of VEGF gene to host liver using UTMD promoted islet revascularisation after islet transplantation and improved the restoration of euglycaemia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism*
  • C-Peptide / blood
  • Gene Transfer Techniques
  • Genetic Vectors
  • Humans
  • Insulin / blood
  • Islets of Langerhans Transplantation*
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Nude
  • Neovascularization, Physiologic / physiology*
  • Plasmids
  • Transplantation, Heterologous
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • Blood Glucose
  • C-Peptide
  • Insulin
  • Vascular Endothelial Growth Factor A