title: Plasma Kallikrein Mediates Vascular Endothelial Growth Factor-Induced Retinal Dysfunction and Thickening.
abstract: Plasma kallikrein is a serine protease and circulating component of inflammation, which exerts clinically significant effects on vasogenic edema. This study examines the role of plasma kallikrein in VEGF-induced retinal edema.
  
  
  
  Intravitreal injections of VEGF and saline vehicle were performed in plasma prekallikrein-deficient (KLKB1-/-) and wild-type (WT) mice, and in both rats and mice receiving a selective plasma kallikrein inhibitor, VA999272. Retinal vascular permeability (RVP) and retinal thickness were measured by Evans blue permeation and optical coherence tomography, respectively. The retinal kallikrein kinin system was examined by Western blotting and immunohistochemistry. Retinal neovascularization was investigated in KLKB1-/- and WT mice subjected to oxygen-induced retinopathy.
  
  
  
  Vascular endothelial growth factor-induced RVP and retinal thickening were reduced in KLKB1-/- mice by 68% and 47%, respectively, compared to VEGF responses in WT mice. Plasma kallikrein also contributes to TNFα-induced retinal thickening, which was reduced by 52% in KLKB1-/- mice. Systemic administration of VA999272 reduced VEGF-induced retinal thickening by 57% (P < 0.001) in mice and 53% (P < 0.001) in rats, compared to vehicle-treated controls. Intravitreal injection of VEGF in WT mice increased plasma prekallikrein in the retina, which was diffusely distributed throughout the inner and outer retinal layers. Avascular and neovascular areas induced by oxygen-induced retinopathy were similar in WT and KLKB1-/- mice.
  
  
  
  Vascular endothelial growth factor increases extravasation of plasma kallikrein into the retina, and plasma kallikrein is required for the full effects of VEGF on RVP and retinal thickening in rodents. Systemic plasma kallikrein inhibition may provide a therapeutic opportunity to treat VEGF-induced retina edema.
authors.affiliation: Joslin Diabetes Center, Boston, Massachusetts, United States 2Beetham Eye Institute, Boston, Massachusetts, United States.
authors.forename: Allen
authors.initials: A
authors.lastname: Clermont
authors.affiliation: Joslin Diabetes Center, Boston, Massachusetts, United States.
authors.forename: Nivetha
authors.initials: N
authors.lastname: Murugesan
authors.affiliation: Joslin Diabetes Center, Boston, Massachusetts, United States.
authors.forename: Qunfang
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Joslin Diabetes Center, Boston, Massachusetts, United States.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kita
authors.affiliation: Vantia Ltd., Southampton, United Kingdom.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Robson
authors.affiliation: Vantia Ltd., Southampton, United Kingdom.
authors.forename: Louise J
authors.initials: LJ
authors.lastname: Rushbrooke
authors.affiliation: Vantia Ltd., Southampton, United Kingdom.
authors.forename: D Michael
authors.initials: DM
authors.lastname: Evans
authors.affiliation: Joslin Diabetes Center, Boston, Massachusetts, United States 2Beetham Eye Institute, Boston, Massachusetts, United States 4Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States.
authors.forename: Lloyd Paul
authors.initials: LP
authors.lastname: Aiello
authors.affiliation: Joslin Diabetes Center, Boston, Massachusetts, United States 5Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States.
authors.forename: Edward P
authors.initials: EP
authors.lastname: Feener
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002199:Capillary Permeability; D058449:Intravitreal Injections; D008269:Macular Edema / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020842:Plasma Kallikrein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D041623:Tomography, Optical Coherence; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000506:poisoning
chemical_list: D042461:Vascular Endothelial Growth Factor A; D020842:Plasma Kallikrein