Prevention of VEGF-mediated microvascular permeability by C-peptide in diabetic mice

Lim, Young-Cheol; Bhatt, Mahendra Prasad; Kwon, Mi-Hye; Park, Donghyun; Lee, Seungkoo; Choe, Jongseon; Hwang, JongYun; Kim, Young-Myeong; Ha, Kwon-Soo
January 2014
Cardiovascular Research;Jan2014, Vol. 101 Issue 1, p155
Academic Journal
Aims Human C-peptide has a beneficial effect on the prevention of diabetic neuropathy, nephropathy, and vascular complications; however, its role in protection against increased vascular permeability in diabetes remains unclear. Our purpose was to explore the potential protective role of C-peptide against microvascular permeability mediated by vascular endothelial growth factor (VEGF)-induced reactive oxygen species (ROS) generation in diabetes. Methods and results Generation of intracellular ROS, real-time changes in intracellular Ca2+, ROS-dependent stress fibre formation, and the disassembly of the adherens junctions were studied by a confocal microscopy in human umbilical vein endothelial cells (HUVECs). VEGF-induced vascular leakage was investigated in the skin of diabetic mice using a Miles vascular permeability assay. Microvascular leakage in the retina of streptozotocin diabetic mice was investigated using a confocal microscopy after left ventricle injection of fluorescein isothiocyanate (FITC)-dextran. C-peptide inhibited the VEGF-induced ROS generation, stress fibre formation, disassembly of vascular endothelial cadherin, and endothelial permeability in HUVECs. Intradermal injection of C-peptide prevented VEGF-induced vascular leakage. Consistent with this, intravitreal injection of C-peptide prevented the extravasation of FITC-dextran in the retinas of diabetic mice, which was also prevented by anti-VEGF antibody and ROS scavengers in diabetic mice. Conclusions/interpretation C-peptide prevents VEGF-induced microvascular permeability by inhibiting ROS-mediated intracellular events in diabetic mice, suggesting that C-peptide replacement is a promising therapeutic strategy to prevent diabetic retinopathy.


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