Deletion of Placental Growth Factor Prevents Diabetic Retinopathy and Is Associated With Akt Activation and HIF1α-VEGF Pathway Inhibition

Abstract

A new diabetic mouse strain, the Akita.PlGF knockout (−/−), was generated to study the role of placental growth factor (PlGF) in the pathogenesis of diabetic retinopathy (DR). PlGF deletion did not affect blood glucose but reduced the body weight of Akita.PlGF−/− mice. Diabetes-induced retinal cell death, capillary degeneration, pericyte loss, and blood-retinal barrier breakdown were prevented in these mice. Protein expression of PlGF was upregulated by diabetes, particularly in vascular cells. Diabetes-induced degradation of ZO-1 and VE-cadherin was reversed due to PlGF deficiency; their expression was correlated with that of sonic hedgehog and angiopoietin-1. PlGF deletion in Akita mice resulted in an increased Akt phosphorylation. Diabetes-activated hypoxia-inducible factor (HIF)1α–vascular endothelial growth factor (VEGF) pathway, including expression of HIF1α, VEGF, VEGFR1–3, and the extent of phospho (p)-VEGFR1, p-VEGFR2, and p–endothelial nitric oxide synthase, was inhibited in the retinas of diabetic PlGF−/− mice. However, expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, CD11b, and CD18 was not inhibited by PlGF deletion, nor was retinal leukostasis. These results suggest that PlGF is critical for the development of DR, and its genetic deletion protects the retina from diabetic damage. Protective mechanisms are associated with Akt activation and HIF1α-VEGF pathway inhibition, but independent of retinal leukostasis in the retinas of diabetic PlGF−/− mice.

Discovery of pan-VEGF inhibitory peptides directed to the extracellular ligand-binding domains of the VEGF receptors

“…For example, studies with animal models indicate that VEGF-B is dispensable for neovascularization but is essential for retinal endothelial cell survival, and antibodies targeting VEGF-B inhibit choroid and retina neovascularization ( 41 ). PlGF has also been implicated in pathological angiogenesis ( 42 , 43 ) and is said to have contributed to the development of diabetic retinopathy ( 44 ). VEGF-C and VEGF-D are expressed in the ischemic retina ( 45 ) and the subretinal vascular membrane of an age-related macular degeneration patient ( 46 ), and blockage of VEGFR-3 with monoclonal antibodies prevents neovascularization in the retina ( 24 ), suggesting that they also contribute to neovascularization in the retina.…”

Therapeutic Effect of Novel Single-Stranded RNAi Agent Targeting Periostin in Eyes with Retinal Neovascularization

“…In this process, the extracellular matrix (ECM) components play a critical role in regulating retinal NV 2 . Previous studies have shown that several growth factors, including the vascular endothelial growth factors (VEGFs), platelet-derived growth factors, transforming growth factor βs, and placenta growth factor, are involved in this process 3, 4, 5, 6. Among these factors, the VEGFs have been well characterized and are known to play a causal role in retinal NV.…”

Treatment strategies for refractory diabetic macular edema: switching anti-VEGF treatments, adopting corticosteroid-based treatments, and combination therapy

“…Bevacizumab, ranibizumab, and aflibercept each have different molecular sizes, binding affinities for VEGF, as well as different half-lives in the vitreous, and this could account for some of the differences noted between these agents. Aflibercept is the only available treatment that targets placental growth factor, which has an unclear role in the pathogenesis of DR, but animal studies suggest that it may contribute to blood-retinal barrier breakdown [45,46].…”