September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Defects in Angiopoietin-Tie2 signaling lead to dose-dependent glaucoma in mice
Author Affiliations & Notes
  • Benjamin R Thomson
    Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Isabel Carota
    Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Tomokazu Souma
    Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Krish Kizhatil
    The Jackson Lab, Bar Harbor, Maine, United States
  • Liang Feng
    Neurobiology, Northwestern University, Evanston, Illinois, United States
  • Xiaorong Liu
    Neurobiology, Northwestern University, Evanston, Illinois, United States
  • Simon W John
    The Jackson Lab, Bar Harbor, Maine, United States
  • Terri L Young
    Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin, United States
  • Susan E. Quaggin
    Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Footnotes
    Commercial Relationships   Benjamin Thomson, None; Isabel Carota, Eli Lilly (E); Tomokazu Souma, Mallinckrodt Pharmaceuticals (F); Krish Kizhatil, None; Liang Feng, None; Xiaorong Liu, None; Simon John, None; Terri Young, None; Susan Quaggin, Aerpio Therapeutics (C), Mannin Research (C)
  • Footnotes
    Support  NIH Grant HL124120
Investigative Ophthalmology & Visual Science September 2016, Vol.57, No Pagination Specified. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to Subscribers Only
      Sign In or Create an Account ×
    • Get Citation

      Benjamin R Thomson, Isabel Carota, Tomokazu Souma, Krish Kizhatil, Liang Feng, Xiaorong Liu, Simon W John, Terri L Young, Susan E. Quaggin; Defects in Angiopoietin-Tie2 signaling lead to dose-dependent glaucoma in mice. Invest. Ophthalmol. Vis. Sci. 201657(12):.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose : Glaucoma is a devastating, progressive optic neuropathy often associated with elevated intraocular pressure (IOP). Despite the high prevalence of disease, few therapies exist as events leading to neurological damage in glaucoma remain obscure. Research into critical mechanisms has been hindered by lack of small animal glaucoma models which develop rapid and reproducible disease. We have shown that disruption of the Angiopoietin (Angpt)-Tie2 signaling pathway in mice results in loss of Schlemm’s canal (SC), elevated IOP and an extreme glaucomatous phenotype. Based on these results, we hypothesized that incomplete disruption of this pathway may lead to milder defects in SC development, less severe ocular hypertension and a progressive glaucoma closely resembling human disease.

Methods : Mice lacking Angpt1 or heterozygous for the Tie2 receptor were generated and aged 8-20 weeks. IOP was measured using a rebound tonometer before euthanasia and tissue harvest. Schlemm’s canal and retina morphology was then assessed using histological methods.

Results : Mice lacking Angpt1 or heterozygous for the Tie2 receptor exhibit a hypoplastic Schlemm’s canal phenotype, with focal narrowing, gaps and convolutions. This misshapen SC is insufficient for normal aqueous humor drainage and Angpt1 KO /Tie2 heterozygous mice exhibit elevated IOP (Angpt1 KO 21.09 mmHg, p<0.001, Tie2 heterozygote 15.39 mmHg p=0.0046) compared to control (12.30 mmHg), with no apparent buphthalmos. Histological analysis revealed progressive glaucoma reminiscent of human disease. As SC defects and glaucoma were caused by partial loss of Tie2 signaling, we attempted a genetic rescue by parallel deletion of the Tie2-regulating phosphatase VE-PTP. Unlike Tie2 heterozygous littermates, Tie2;VE-PTP double-heterozygous mice had normal IOP and did not develop disease, demonstrating that Tie2 activation through inhibition of a negative regulator prevents glaucoma pathogenesis.

Conclusions : Angpt/Tie2 signaling has a dose-dependent effect on SC development and IOP. Using inducible knockout systems we have created several novel mouse glaucoma models with variable onset and severity. In addition, we have identified a potential therapeutic target, VE-PTP, which can directly impact canal function. Pharmacological inhibition of VE-PTP leads to increased Angpt/Tie2 signaling activity and may provide an effective tool for increasing SC function in patients with glaucoma.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×