title: Prostate specific membrane antigen (PSMA) regulates angiogenesis independently of VEGF during ocular neovascularization.
abstract: BACKGROUND
  Aberrant growth of blood vessels in the eye forms the basis of many incapacitating diseases and currently the majority of patients respond to anti-angiogenic therapies based on blocking the principal angiogenic growth factor, vascular endothelial growth factor (VEGF). While highly successful, new therapeutic targets are critical for the increasing number of individuals susceptible to retina-related pathologies in our increasingly aging population. Prostate specific membrane antigen (PSMA) is a cell surface peptidase that is absent on normal tissue vasculature but is highly expressed on the neovasculature of most solid tumors, where we have previously shown to regulate angiogenic endothelial cell invasion. Because pathologic angiogenic responses are often triggered by distinct signals, we sought to determine if PSMA also contributes to the pathologic angiogenesis provoked by hypoxia of the retina, which underlies many debilitating retinopathies.
  
  
  RESULTS
  Using a mouse model of oxygen-induced retinopathy, we found that while developmental angiogenesis is normal in PSMA null mice, hypoxic challenge resulted in decreased retinal vascular pathology when compared to wild type mice as assessed by avascular area and numbers of vascular tufts/glomeruli. The vessels formed in the PSMA null mice were more organized and highly perfused, suggesting a more 'normal' phenotype. Importantly, the decrease in angiogenesis was not due to an impaired hypoxic response as levels of pro-angiogenic factors are comparable; indicating that PSMA regulation of angiogenesis is independent of VEGF. Furthermore, both systemic and intravitreal administration of a PSMA inhibitor in wild type mice undergoing OIR mimicked the PSMA null phenotype resulting in improved retinal vasculature.
  
  
  CONCLUSIONS
  Our data indicate that PSMA plays a VEGF-independent role in retinal angiogenesis and that the lack of or inhibition of PSMA may represent a novel therapeutic strategy for treatment of angiogenesis-based ocular diseases.
authors: University of Connecticut Health Center, Farmington, Connecticut, United States of America.
authors: Christina L
authors: CL
authors: Grant
authors: Leslie A
authors: LA
authors: Caromile
authors: Vivienne
authors: V
authors: Ho
authors: Khayyam
authors: K
authors: Durrani
authors: M Mamunur
authors: MM
authors: Rahman
authors: Kevin P
authors: KP
authors: Claffey
authors: Guo-Hua
authors: GH
authors: Fong
authors: Linda H
authors: LH
authors: Shapiro
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000096:biosynthesis*; D002462:Cell Membrane / Q000378:metabolism; D005786:Gene Expression Regulation; D043425:Glutamate Carboxypeptidase II / Q000096:biosynthesis*; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism; D010447:Peptide Hydrolases / Q000737:chemistry; D010477:Perfusion; D010641:Phenotype; D012160:Retina / Q000378:metabolism / Q000473:pathology; D015861:Retinal Neovascularization / Q000378:metabolism*; D012169:Retinal Vein / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D000954:Antigens, Surface; D042461:Vascular Endothelial Growth Factor A; D010447:Peptide Hydrolases; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D010100:Oxygen