title: SRPK1 inhibition modulates VEGF splicing to reduce pathological neovascularization in a rat model of retinopathy of prematurity.
abstract: OBJECTIVE
  We tested the hypothesis that recombinant human VEGF-A165b and the serine arginine protein kinase (SRPK) inhibitor, SRPIN340, which controls splicing of the VEGF-A pre-mRNA, prevent neovascularization in a rodent model of retinopathy of prematurity (ROP).
  
  
  METHODS
  In the 50/10 oxygen-induced retinopathy (50/10 OIR) model that exposes newborn rats to repeated cycles of 24 hours of 50% oxygen alternating with 24 hours of 10% oxygen, pups received intraocular injections of SRPIN340, vehicle, VEGF165b, anti-VEGF antibody, or saline. Whole mounts of retinas were prepared for isolectin immunohistochemistry, and preretinal or intravitreal neovascularization (PRNV) determined by clock hour analysis.
  
  
  RESULTS
  The anti-VEGF antibody (P < 0.04), rhVEGF165b (P < 0.001), and SRPIN340 (P < 0.05) significantly reduced PRNV compared with control eyes. SRPIN340 reduced the expression of proangiogenic VEGF165 without affecting VEGF165b expression.
  
  
  CONCLUSIONS
  These results suggest that splicing regulation through selective downregulation of proangiogenic VEGF isoforms (via SRPK1 inhibition) or competitive inhibition of VEGF signaling by rhVEGF165b has the potential to be an effective alternative to potential cyto- and neurotoxic anti-VEGF agents in the treatment of pathological neovascularization in the eye.
authors.affiliation: Microvascular Research Laboratories, School of Physiology and Pharmacology, University of Bristol, Bristol, UK.
authors.forename: Melissa V R
authors.initials: MV
authors.lastname: Gammons
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Dick
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Harper
authors.forename: David O
authors.initials: DO
authors.lastname: Bates
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D056965:Injections, Intraocular; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015861:Retinal Neovascularization / Q000188:drug therapy*; D012178:Retinopathy of Prematurity; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D010880:Piperidines; D047428:Protein Kinase Inhibitors; C584061:SRPIN340; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D017346:Protein Serine-Threonine Kinases
keywords: VEGF; angiogenesis; retinopathy of prematurity; splicing