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

Abstract:

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 Ca(2+), 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.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Lim YC,Bhatt MP,Kwon MH,Park D,Lee S,Choe J,Hwang J,Kim YM,Ha KS

doi

10.1093/cvr/cvt238

subject

Has Abstract

pub_date

2014-01-01 00:00:00

pages

155-64

issue

1

eissn

0008-6363

issn

1755-3245

pii

cvt238

journal_volume

101

pub_type

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