Abstract: TH-PO393

Calcium Dobesilate Reduces VEGF Signaling in Endothelial Cells, Preserves Cell Function, and Improves Vascular Complications in Diabetic Mice

Session Information

Category: Cell Biology

  • 203 Growth Factors, Chemokines, Autacoids

Authors

  • Njau, Florence, Hannover Medical School, Hannover, Germany
  • Shushakova, Nelli, Nephrology and Hypertensiology, 30625 Hannover, Germany
  • Park, Joon-Keun, Hannover Medical School, Hannover, Germany
  • Menne, Jan, Medical School Hannover, Hannover, Germany
  • Haller, Hermann G., Hannover Medical School, Hannover, Germany
Background

Calcium dobesilate is a small molecule with vasoprotective properties. Preliminary evidence suggests that calcium dobesilate interferes with heparan-sulfate binding sites of growth factors such as FGF and VEGF. We therefore tested the hypothesis that calcium dobesilate (1) ameliorates diabetic nephropathy and (2) directly and/or indirectly inhibits VEGF signaling in the microcirculation.

Methods

In vitro HUVECs were used for analysis of VEGF signaling as well as migration and proliferation. Streptozotocin-treated mice (STZ) were treated with calcium dobesilate and analyzed after 4 and 8 weeks of hyperglycemia. Diabetic neuropathy was assessed by thermal sensitivity Urinary albumin was measured by. ELISA and immunohistochemistry performed on cryostat or on paraffin sections.

Results

Dobesilate (100 and 200 μM) decreased VEGF (20 ng/ml)-induced migration by 50% and inhibited assembly of F-actin in lamellipodia-like structures and phosphorylation of focal adhesion kinase (FAK). Dobesilate reduced HUVECs proliferation by 30% and enhanced apoptosis of HUVECs induced by serum deprivation in a dose-dependent manner as evidenced by a decrease in Bcl-2/Bax ratio, and phosphorylation of Bad. It inhibited VEGF-induced phosphorylation of VEGFR2 kinase by 50% in concentration dependent manner and suppressed the phosphorylation of pERK1/2, pMEK1/2 and Pp38 MAPK. Diabetic mice treated with calcium dobesilate showed a decrease in albuminuria, less phosphorylation of VEGF-R2 and an increased thermal sensitivity as compared to sham-treated diabetic animals.

Conclusion

Calcium dobesilate ameliorates both hyperglycemia-induced nephropathy and neuropathy in mice. In vitro the signaling of VEGF in endothelial cells is reduced. Our findings suggest that calcium dobesilate is a VEGF inhibitor at high concentrations. The specific inhibition of FGF and VEGF signaling by blockading heparin sulfate binding sites may be a novel therapeutic strategy for diabetic vascular complications.

Funding

  • Government Support - Non-U.S.