title: Intravitreal injection of TIMP3 or the EGFR inhibitor erlotinib offers protection from oxygen-induced retinopathy in mice.
abstract: OBJECTIVE
  Pathological neovascularization is a crucial component of proliferative retinopathies. Previous studies showed that inactivation of A disintegrin and metalloproteinase 17 (ADAM17), a membrane-anchored metalloproteinase that regulates epidermal growth factor receptor (EGFR) signaling, reduces pathological retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR). Here, we tested how genetic inactivation of a physiological ADAM17 inhibitor, the tissue inhibitor of matrix metalloproteinases-3 (TIMP3), or intravitreal injection of TIMP3 or of the EGFR inhibitor erlotinib influenced the outcome of OIR.
  
  
  METHODS
  Wild-type mice were subjected to OIR in a chamber with 75% oxygen for 5 days beginning at postnatal day 7 (P7). Upon removal from the oxygen chamber at P12, they received a single intravitreal injection of TIMP3, erlotinib, or control. The central avascular area and neovascular tufts were measured after 5 days in room air (21% oxygen) at P17. Moreover, OIR experiments were performed with Timp3-/- mice and littermate controls.
  
  
  RESULTS
  Timp3-/- mice showed greater revascularization of the central avascular area and developed equal or fewer neovascular tufts compared to littermate controls, depending on the genetic background. Wild-type mice injected with TIMP3 or erlotinib developed fewer neovascular tufts when compared to untreated littermates. Moreover, vessel regrowth into the avascular area was reduced in TIMP3-injected mice, but not in erlotinib-injected mice.
  
  
  CONCLUSIONS
  These studies demonstrate that TIMP3 and erlotinib inhibit pathological neovascularization in the mouse retina, most likely due to inactivation of ADAM17 and the EGFR, respectively. Thus, TIMP3 and erlotinib emerge as attractive candidate antiangiogenic compounds for prevention and treatment of proliferative retinopathies.
authors.affiliation: Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York 10021, USA.
authors.forename: Nina Jasmin
authors.initials: NJ
authors.lastname: Hewing
authors.forename: Gisela
authors.initials: G
authors.lastname: Weskamp
authors.forename: Joost
authors.initials: J
authors.lastname: Vermaat
authors.forename: Eric
authors.initials: E
authors.lastname: Farage
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Glomski
authors.forename: Steven
authors.initials: S
authors.lastname: Swendeman
authors.forename: Robison Vernon Paul
authors.initials: RV
authors.lastname: Chan
authors.forename: Michael F
authors.initials: MF
authors.lastname: Chiang
authors.forename: Rama
authors.initials: R
authors.lastname: Khokha
authors.forename: Bela
authors.initials: B
authors.lastname: Anand-Apte
authors.forename: Carl Peter
authors.initials: CP
authors.lastname: Blobel
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005260:Female; D058449:Intravitreal Injections; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D010100:Oxygen / Q000633:toxicity; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D012164:Retinal Diseases / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000494:pharmacology*
chemical_list: D020533:Angiogenesis Inhibitors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D019717:Tissue Inhibitor of Metalloproteinase-3; D000069347:Erlotinib Hydrochloride; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D010100:Oxygen