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.

The Acknowledgments should read as follows: The authors thank Dr. Zhenhua Xu, Wilmer Eye Institute, for her helpful discussions about the WB experiments, and Dr. Junsong Gong, Wilmer Eye Institute, for his technical assistance. The Author Contributions should read as follows: H.H. designed the study, performed experiments, interpreted data, and wrote the manuscript. J.H., D.J., Y.W., Y.L., S.W., and E.J.D. performed experiments and interpreted data. G.A.L. and R.D.S. discussed the study and reviewed and edited the manuscript. P.C. generated and provided the PlGF knockout mice. H.H. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The online version reflects these changes.

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