title: Regulation of ocular angiogenesis by Notch signaling: implications in neovascular age-related macular degeneration.
abstract: OBJECTIVE
  Wet age-related macular degeneration (AMD), which accounts for most AMD-related vision loss, is characterized by choroidal neovascularization (CNV). The underlying mechanism of CNV is poorly understood, but evidence indicates pathologic recruitment of normal angiogenic signaling pathways such as the VEGF pathway. Recent evidence suggests that the VEGF pathway regulates angiogenesis in concert with Notch signaling. Here, the authors examined the role of Notch signaling in CNV in the backdrop of Notch signaling-mediated regulation of retinal angiogenesis.
  
  
  METHODS
  Choroid sclera complexes, after laser-induced CNV, were examined for changes in CNV lesion volume and in proangiogenic and antiangiogenic gene expression after perturbation in Notch signaling. Retinal vessels and angiogenic gene expression in retinal endothelial cells were analyzed in postnatal rats after perturbations in Notch signaling. Notch signaling was activated and inhibited by intravitreal or systemic injection of Jagged1 peptide and gamma secretase inhibitor DAPT, respectively.
  
  
  RESULTS
  The authors demonstrated that activation of the canonical Notch pathway reduced the volume of CNV lesions as it attenuated the development of postnatal retinal vasculature. In contrast, inhibition of the Notch pathway exacerbated CNV lesions as it led to the development of hyperdense retinal vasculature. The authors also identified genes associated with proangiogenesis (Vegfr2, Ccr3, and Pdgfb) and antiangiogenesis (Vegfr1 and Unc5b) as targets of Notch signaling-mediated vascular homeostasis, the disruption of which might underlie CNV.
  
  
  CONCLUSIONS
  This study suggests that Notch signaling is a key regulator of CNV and thus a molecular target for therapeutic intervention in wet AMD.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198-5840, USA. iahmad@unmc.edu
authors.forename: Iqbal
authors.initials: I
authors.lastname: Ahmad
authors.forename: Sudha
authors.initials: S
authors.lastname: Balasubramanian
authors.forename: Carolina B
authors.initials: CB
authors.lastname: Del Debbio
authors.forename: Sowmya
authors.initials: S
authors.lastname: Parameswaran
authors.forename: Allen R
authors.initials: AR
authors.lastname: Katz
authors.forename: Carol
authors.initials: C
authors.lastname: Toris
authors.forename: Robert N
authors.initials: RN
authors.lastname: Fariss
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000494:pharmacology; D020256:Choroidal Neovascularization / Q000378:metabolism* / Q000473:pathology; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D005451:Fluorescein Angiography; D005786:Gene Expression Regulation / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D054397:Receptors, CCR3; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015861:Retinal Neovascularization / Q000378:metabolism* / Q000473:pathology; D012171:Retinal Vessels / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2; D057135:Wet Macular Degeneration / Q000378:metabolism* / Q000473:pathology
chemical_list: D002135:Calcium-Binding Proteins; C515352:Ccr3 protein, rat; D004151:Dipeptides; D036341:Intercellular Signaling Peptides and Proteins; C000606275:Jag1 protein, rat; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D020574:Proto-Oncogene Proteins c-sis; D054397:Receptors, CCR3; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2