title: Inhibition of ocular neovascularization by co-inhibition of VEGF-A and PLGF.
abstract: OBJECTIVE
  Age-related macular degeneration (AMD) appears to be a disease with increasing incidence in Western countries and may develop into acquired blindness. Choroidal neovascularization (CNV) is the most frequent cause for AMD, and is commonly induced by regional inflammation. Past studies have highlighted vascular endothelial growth factor A (VEGF-A) as a major trigger for CNV. However, studies on the associated angiogenic factors other than VEGF-A are lacking.
  
  
  METHODS
  Here, we used a well-established laser burn (LB)-induced experimental CNV mouse model to study the molecular mechanisms underlying the development of CNV after ocular injury. We analyzed vessel density by lectin labeling. We isolated macrophages, endothelial cells and other cell types by flow cytometry, and analyzed levels of different angiogenic factors in these populations. We used antisera against VEGF-A (aVEGF) and/or antisera against placental growth factor (PLGF; aPLGF) to antagonize CNV. We used an antibody-driven toxin to selectively eliminate macrophages to evaluate the role of macrophages in CNV. We also examined expression of PLGF in macrophage subtypes.
  
  
  RESULTS
  The choroidal vessel density increased significantly 7 days after LB. LB increased significantly the levels of VEGF-A and PLGF in mouse eyes. Treatment with aVEGF significantly blunted increases in vessel density by LB. Treatment with aPLGF alone did not significantly reduce increases in vessel density. However, aPLGF significantly increased the inhibitory effects of aVEGF on vessel density increases. While VEGF-A was produced by endothelial cells, macrophages and other types at similar levels, PLGF seemed to be predominantly produced by macrophages. Selective macrophage depletion significantly reduced CNV. M2, but M1 macrophages produced high levels of PLGF.
  
  
  CONCLUSIONS
  Together, our data suggest a previously unappreciated role of PLGF in coordination with VEGF-A to regulate CNV during ocular injury. Our study highlights macrophages and their production of PLGF as novel targets for CNV therapy.
authors.affiliation: Department of Interventional Neuroradiology, Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Huo
authors.forename: Youxiang
authors.initials: Y
authors.lastname: Li
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Jiang
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Sun
authors.forename: Lixue
authors.initials: L
authors.lastname: Gu
authors.forename: Wenshi
authors.initials: W
authors.lastname: Guo
authors.forename: Dapeng
authors.initials: D
authors.lastname: Sun
mesh_terms: D000818:Animals; D020256:Choroidal Neovascularization / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005123:Eye / Q000378:metabolism / Q000528:radiation effects; D005260:Female; D007834:Lasers; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor