June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Deletion of Placental Growth Factor Prevents Diabetic Retinopathy and Is Associated With Akt Activation and HIF1alpha-VEGF Pathway Inhibition
Author Affiliations & Notes
  • Hu Huang
    Ophthalmology, Johns Hopkins Wilmer Eye Inst, Baltimore, MD
  • Footnotes
    Commercial Relationships Hu Huang, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 5853. doi:
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      Hu Huang; Deletion of Placental Growth Factor Prevents Diabetic Retinopathy and Is Associated With Akt Activation and HIF1alpha-VEGF Pathway Inhibition. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5853.

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Abstract
 
Purpose
 

To study the role of placental growth factor (PlGF) in the pathogenesis of diabetic retinopathy (DR).

 
Methods
 

Akita diabetic mice and PlGF-/- mice were crossed to generate the Akita.PlGF-/- mice. Retinal vasculatures were isolated by trypsin digestion. Blood-retinal barrier (BRB) breakdown was assessed by the leakage of ³H-mannitol into the retina. Apoptotic cell death was analyzed by TUNEL staining and cell death ELISA. Retinal leukostasis was assessed by FITC-conjugated ConA labeling method. The expression levels of protein and mRNA were measured by Western blots and real-time PCR, respectively.The cellular localizations of protein and phosphorylated protein were detected by immunofluorescence staining and confocal microscopy,

 
Results
 

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 zonula occludens (ZO)-1 and vascular endothelial (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 (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, CD11b, and CD18 was not inhibited by PlGF deletion, nor was retinal leukostasis.

 
Conclusions
 

The 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.  

 

 
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