Dioscin Reduces Vascular Damage in the Retina of db/db Mice by Inhibiting the VEGFA Signaling Pathway.

Jun Wang,Guang Yan Yang,Hui Pan Zhao,Ming Ming Yang,Ting Meng,Chu Chu Cheng,Xiao Ling Luo,Hong Yan Sun

doi:10.3389/fphar.2021.811897

Abstract

Diabetic retinopathy (DR) is a complication of diabetes that has a serious impact on the quality of life of patients. VEGFA is necessary in the physiological state to maintain endothelial activity and physical properties of blood vessels. VEGFA plays an important role in the promotion of neovascularization; therefore, inhibition of VEGFA can degrade the structure of blood vessels and reduce neovascularization. In the present study, HERB, a high-throughput experimental and reference-oriented database of herbal medicines, was used for compound mining targeting VEGFA. The compounds most likely to interact with VEGFA were screened by molecular docking. Next, the compounds were used to verify whether it could inhibit the activity of the VEGF signaling pathway in vitro and neovascularization in vivo. In vitro, we found that dioscin could inhibit the activation of the VEGFA–VEGFR2 signaling pathway and cell proliferation of human retinal microvascular endothelial cells in a high-glucose (HG) environment. A more important dioscin intervention inhibits the expression of pro-angiogenic factors in the retinas of db/db mice. In conclusion, our study indicates that dioscin reduces the vascular damage and the expression of pro-angiogenic factors in the retina of db/db mice and implies an important and potential application of dioscin for treatment of DR in clinics.

Highlights

Diabetes mellitus is a rapidly growing global disease that affects approximately 415 million people and is expected to reach 642 million by 2040 (Saeedi et al, 2019)
Molecular docking analysis revealed that dioscin was the most likely compound to interact with VEGFA and that the main factors sustaining their amino acid interactions were hydrogen bonds, van der Waals forces, and alkyl groups (Figure 1B)
Our results showed that bevacizumab or dioscin treatment significantly decreased the phosphorylation levels of vascular endothelial growth factor receptor 2 (VEGFR2) and Akt when compared with the control group (Figure 4A)

Summary

Introduction

Diabetes mellitus is a rapidly growing global disease that affects approximately 415 million people and is expected to reach 642 million by 2040 (Saeedi et al, 2019). Ischemia and hypoxia cause excessive production of VEGF by retinal epithelial cells, endothelial cells, and the retinal pigment epithelium, while VEGF recruits leukocyte adhesion to aggravate ischemia and hypoxia, Abbreviations: B7-H3, B7 homolog 3; CIE, -CDOCKER interaction energy; DR, diabetic retinopathy; ECs, endothelial cells; FOXO1, Forkhead box protein O1A; HG, high glucose; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; VEGFR1, vascular endothelial growth factor receptor 1; VEGFR2, vascular endothelial growth factor receptor 2. Overexpression of VEGF leads to proliferation of the retinal pigment epithelium, proliferation of vascular endothelial cells, and increased permeability; this promotes the activation of inflammatory factors, leading to retinal hemorrhage, exudation, and macular edema, and can even lead to the formation of neovascularization (Osaadon et al, 2014). VEGF plays an important role in the formation of neovascularization; inhibition of VEGF can degrade the structure of blood vessels and reduce neovascularization (Ajlan et al, 2016)

Methods

Results

Conclusion