Calcium dobesilate reduces VEGF signaling by interfering with heparan sulfate binding site and protects from vascular complications in diabetic mice

Abstract

Inhibiting vascular endothelial growth factor (VEGF) is a therapeutic option in diabetic microangiopathy. However, VEGF is needed at physiological concentrations to maintain glomerular integrity; complete VEGF blockade has deleterious effects on glomerular structure and function. Anti-VEGF therapy in diabetes raises the challenge of reducing VEGF-induced pathology without accelerating endothelial cell injury. Heparan sulfate (HS) can act as a co-receptor for VEGF. Calcium dobesilate (CaD) is a small molecule with vasoprotective properties that has been used for the treatment of diabetic microangiopathy. Preliminary evidence suggests that CaD interferes with HS binding sites of fibroblast growth factor. We therefore tested the hypotheses that (1) CaD inhibits VEGF signaling in endothelial cells, (2) that this effect is mediated via interference between CaD and HS, and (3) that CaD ameliorates diabetic nephropathy in a streptozotocin-induced diabetic mouse model by VEGF inhibition. We found that CaD significantly inhibited VEGF165-induced endothelial cell migration, proliferation, and permeability. CaD significantly inhibited VEGF165-induced phosphorylation of VEGFR-2 and suppressed the activity of VEGFR-2 mediated signaling cascades. The effects of CaD in vitro were abrogated by heparin, suggesting the involvement of heparin-like domain in the interaction with CaD. In addition, VEGF121, an isoform which does not bind to heparin, was not inhibited by CaD. By applying proximity ligation assays to endothelial cells, we show inhibition of interaction in situ between HS and VEGF and between VEGF and VEGFR-2. Moreover, CaD reduced VEGF signaling in diabetic kidneys and ameliorated diabetic nephropathy and neuropathy, suggesting CaD as a VEGF inhibitor without the negative effects of complete VEGF blockade and therefore could be useful as a strategy in treating diabetic nephropathy.

Qishen Yiqi Dripping Pill Protects Diabetic Nephropathy by Inhibiting the PI3K-AKT Signaling Pathways in Rats

“…Changes in its expression or activity are involved in the development of diabetes and DN [25]. VEGF-A is an important regulator of angiogenesis and vascular permeability and may play a pathogenic role in DN [26]. When VEGF-A expression is below normal levels, podocytes are damaged [27].…”

Intravitreal Ranibizumab Alone or in Combination with Calcium Dobesilate for the Treatment of Diabetic Macular Edema in Nonproliferative Diabetic Retinopathy Patients: 12-Month Outcomes of a Retrospective Study

“…Accordingly, anti-VEGF and anti-inflammatory agents are considered the first-line treatments for DME [42,43] and show good outcomes [44,45]. CaD downregulates VEGF and inhibits VEGF-related pathways and may work synergistically with anti-VEGF agents [46]. is might partly explain why oral CaD alone has no therapeutic effect on DME, but it reduced the number of intravitreal injections required when combined with anti-VEGF agents during the 1-year follow-up period of this study.…”