title: Phosphomannopentaose sulfate (PI-88) suppresses angiogenesis by downregulating heparanase and vascular endothelial growth factor in an oxygen-induced retinal neovascularization animal model.
abstract: OBJECTIVE
  Vascular endothelial growth factor (VEGF) is the most potent angiogenic mitogen, and has been associated with angiogenesis. Heparanase is an endoglycosidase that specifically cleaves heparan sulfate side chains, which can induce VEGF expression. The aims of the present study were to evaluate the heparanase expression and its relationship with VEGF in the retina of oxygen-induced retinopathy (OIR) mice, and to investigate the effect of the heparanase inhibitor phosphomannopentaose sulfate (PI-88) in the OIR retinas.
  
  
  METHODS
  Seventy-seven newborn C57BL/6 mice were involved in this study. On postnatal day 7 (P7), pups were exposed to a hyperoxia condition (75% oxygen) for 5 days, and on P12, the mice were returned to room air. Control mice were exposed to room air from birth until P17, with normally developing retinal vasculature. PI-88 was administered intraperitoneally to OIR mice at a dose of 35.7 mg/kg/day for 5 consecutive days. The expression level of heparanase and VEGF in the retinas was assayed using immunohistochemistry, Q-RT-PCR, and western blot.
  
  
  RESULTS
  The expression levels of heparanase and VEGF were increased in the OIR retinas compared with the control mice. The Q-RT-PCR results showed that the mRNA expression levels of heparanase and VEGF in OIR retina were increased 1.71 fold (p<0.0001) and 4.34 fold (p<0.0001), respectively. The western blot results showed that the protein expression levels of heparanase and VEGF were increased 1.49 fold (p<0.0001) and 1.72 fold (p<0.0001), respectively, in the OIR retinas compared with the normal retinas. The immunohistochemistry analysis revealed that the heparanase and VEGF signals were intense in the retinal vascular endothelia of the OIR mice but faint in those of the normal controls. The increased protein and mRNA expression levels of heparanase and VEGF in the mouse retinas were significantly decreased by PI-88 administration (p<0.0001).
  
  
  CONCLUSIONS
  Heparanase expression was upregulated and correlated with an increase in VEGF expression in the OIR mouse retinas, and might be involved in the progress of retinopathy of prematurity. Inhibition of heparanase expression by PI-88 could be used as a novel therapeutic method for retinopathy of prematurity.
authors: The State Key Laboratory of Ophthalmology Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China.
authors: Xian-Jun
authors: XJ
authors: Liang
authors: Ling
authors: L
authors: Yuan
authors: Jie
authors: J
authors: Hu
authors: Hong-Hua
authors: HH
authors: Yu
authors: Tao
authors: T
authors: Li
authors: Shao-Fen
authors: SF
authors: Lin
authors: Shi-Bo
authors: SB
authors: Tang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D015536:Down-Regulation; D005966:Glucuronidase / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D007274:Injections, Intraperitoneal; D051379:Mice; D008810:Mice, Inbred C57BL; D009844:Oligosaccharides / Q000008:administration & dosage / Q000627:therapeutic use*; D010100:Oxygen / Q000009:adverse effects; D015861:Retinal Neovascularization / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D012178:Retinopathy of Prematurity / Q000378:metabolism / Q000517:prevention & control; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D009844:Oligosaccharides; D010100:Oxygen; D042461:Vascular Endothelial Growth Factor A; D000099175:Heparanase; C120158:phosphomannopentaose sulfate; C467480:vascular endothelial growth factor A, mouse