title: Ghrelin modulates physiologic and pathologic retinal angiogenesis through GHSR-1a.
abstract: OBJECTIVE
  Vascular degeneration and the ensuing abnormal vascular proliferation are central to proliferative retinopathies. Given the metabolic discordance associated with these diseases, the authors explored the role of ghrelin and its growth hormone secretagogue receptor 1a (GHSR-1a) in proliferative retinopathy.
  
  
  METHODS
  In a rat model of oxygen-induced retinopathy (OIR), the contribution of ghrelin and GHSR-1a was investigated using the stable ghrelin analogs [Dap3]-ghrelin and GHRP6 and the GSHR-1a antagonists JMV-2959 and [D-Lys3]-GHRP-6. Plasma and retinal levels of ghrelin were analyzed by ELISA, whereas retinal expression and localization of GHSR-1a were examined by immunohistochemistry and Western blot analysis. The angiogenic and vasoprotective properties of ghrelin and its receptor were further confirmed in aortic explants and in models of vaso-obliteration.
  
  
  RESULTS
  Ghrelin is produced locally in the retina, whereas GHSR-1a is abundantly expressed in retinal endothelial cells. Ghrelin levels decrease during the vaso-obliterative phase and rise during the proliferative phase of OIR. Intravitreal delivery of [Dap3]-ghrelin during OIR significantly reduces retinal vessel loss when administered during the hyperoxic phase. Conversely, during the neovascular phase, ghrelin promotes pathologic angiogenesis through the activation of GHSR-1a. These angiogenic effects were confirmed ex vivo in aortic explants.
  
  
  CONCLUSIONS
  New roles were disclosed for the ghrelin-GHSR-1a pathway in the preservation of retinal vasculature during the vaso-obliterative phase of OIR and during the angiogenic phase of OIR. These findings suggest that the ghrelin-GHSR-1a pathway can exert opposing effects on retinal vasculature, depending on the phase of retinopathy, and thus holds therapeutic potential for proliferative retinopathies.
authors.affiliation: Department of Pediatrics, Hôpital Sainte-Justine Research Center, Montreal, Quebec, Canada.
authors.forename: Karine
authors.initials: K
authors.lastname: Zaniolo
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Sapieha
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Shao
authors.forename: Andreas
authors.initials: A
authors.lastname: Stahl
authors.forename: Tang
authors.initials: T
authors.lastname: Zhu
authors.forename: Sophie
authors.initials: S
authors.lastname: Tremblay
authors.forename: Emilie
authors.initials: E
authors.lastname: Picard
authors.forename: Ankush
authors.initials: A
authors.lastname: Madaan
authors.forename: Martine
authors.initials: M
authors.lastname: Blais
authors.forename: Pierre
authors.initials: P
authors.lastname: Lachapelle
authors.forename: Joseph
authors.initials: J
authors.lastname: Mancini
authors.forename: Pierre
authors.initials: P
authors.lastname: Hardy
authors.forename: Lois E H
authors.initials: LE
authors.lastname: Smith
authors.forename: Huy
authors.initials: H
authors.lastname: Ong
authors.forename: Sylvain
authors.initials: S
authors.lastname: Chemtob
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D019084:Fluorescent Antibody Technique, Indirect; D054439:Ghrelin / Q000494:pharmacology*; D006801:Humans; D007231:Infant, Newborn; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D058449:Intravitreal Injections; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D018384:Oxidative Stress; D010100:Oxygen / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015861:Retinal Neovascularization / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D012171:Retinal Vessels / Q000502:physiology*; D012178:Retinopathy of Prematurity / Q000139:chemically induced; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D054439:Ghrelin; D054440:Receptors, Ghrelin; D042461:Vascular Endothelial Growth Factor A; C548904:insulin-like growth factor-1, rat; C467498:vascular endothelial growth factor A, rat; D007334:Insulin-Like Growth Factor I; D010100:Oxygen