Regulation of ocular angiogenesis by notch signaling

Implications in neovascular age-related macular degeneration

Iqbal Ahmad, Sudha Balasubramanian, Carolina B. del Debbio, Sowmya Parameswaran, Allen R. Katz, Carol B Toris, Robert N. Fariss

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

PURPOSE. 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.

Original languageEnglish (US)
Pages (from-to)2868-2878
Number of pages11
JournalInvestigative Ophthalmology and Visual Science
Volume52
Issue number6
DOIs
StatePublished - May 1 2011

Fingerprint

Choroidal Neovascularization
Macular Degeneration
Vascular Endothelial Growth Factor A
Gene Expression
Retinal Vessels
Amyloid Precursor Protein Secretases
Sclera
Choroid
Blood Vessels
Lasers
Homeostasis
Endothelial Cells
Peptides
Injections

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Regulation of ocular angiogenesis by notch signaling : Implications in neovascular age-related macular degeneration. / Ahmad, Iqbal; Balasubramanian, Sudha; del Debbio, Carolina B.; Parameswaran, Sowmya; Katz, Allen R.; Toris, Carol B; Fariss, Robert N.

In: Investigative Ophthalmology and Visual Science, Vol. 52, No. 6, 01.05.2011, p. 2868-2878.

Research output: Contribution to journalArticle

Ahmad, Iqbal ; Balasubramanian, Sudha ; del Debbio, Carolina B. ; Parameswaran, Sowmya ; Katz, Allen R. ; Toris, Carol B ; Fariss, Robert N. / Regulation of ocular angiogenesis by notch signaling : Implications in neovascular age-related macular degeneration. In: Investigative Ophthalmology and Visual Science. 2011 ; Vol. 52, No. 6. pp. 2868-2878.
@article{75de8095b7484578ba3952b81d5d9211,
title = "Regulation of ocular angiogenesis by notch signaling: Implications in neovascular age-related macular degeneration",
abstract = "PURPOSE. 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.",
author = "Iqbal Ahmad and Sudha Balasubramanian and {del Debbio}, {Carolina B.} and Sowmya Parameswaran and Katz, {Allen R.} and Toris, {Carol B} and Fariss, {Robert N.}",
year = "2011",
month = "5",
day = "1",
doi = "10.1167/iovs.10-6608",
language = "English (US)",
volume = "52",
pages = "2868--2878",
journal = "Investigative Ophthalmology and Visual Science",
issn = "0146-0404",
publisher = "Association for Research in Vision and Ophthalmology Inc.",
number = "6",

}

TY - JOUR

T1 - Regulation of ocular angiogenesis by notch signaling

T2 - Implications in neovascular age-related macular degeneration

AU - Ahmad, Iqbal

AU - Balasubramanian, Sudha

AU - del Debbio, Carolina B.

AU - Parameswaran, Sowmya

AU - Katz, Allen R.

AU - Toris, Carol B

AU - Fariss, Robert N.

PY - 2011/5/1

Y1 - 2011/5/1

N2 - PURPOSE. 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.

AB - PURPOSE. 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.

UR - http://www.scopus.com/inward/record.url?scp=79955979616&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79955979616&partnerID=8YFLogxK

U2 - 10.1167/iovs.10-6608

DO - 10.1167/iovs.10-6608

M3 - Article

VL - 52

SP - 2868

EP - 2878

JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

SN - 0146-0404

IS - 6

ER -