March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Ang II Subtype 2 Receptor (AT2R) Activation By Compound 21 Reduces Endothelial Cell Migration in vitro and Neovascularization in the Oxygen-induced Retinopathy (OIR) Model
Author Affiliations & Notes
  • Sergio Li Calzi
    Pharmacology and Therapeutics,
    University of Florida, Gainesville, Florida
  • Lynn C. Shaw
    Pharmacology and Therapeutics,
    University of Florida, Gainesville, Florida
  • Tatiana Salazar
    Pharmacology and Therapeutics,
    University of Florida, Gainesville, Florida
  • Colin Sumners
    Physiology and Functional Genomics,
    University of Florida, Gainesville, Florida
  • Julia Busik
    Physiology, Michigan State University, East Lansing, Michigan
  • Mohan Raizada
    Physiology and Functional Genomics,
    University of Florida, Gainesville, Florida
  • Maria Tikhonenko
    Physiology, Michigan State University, East Lansing, Michigan
  • Ulrike Steckelings
    Center for Cardiovascular Research, Universitatsmedzin Berlin, Berlin, Germany
  • Maria B. Grant
    Pharmacology and Therapeutics,
    University of Florida, Gainesville, Florida
  • Footnotes
    Commercial Relationships  Sergio Li Calzi, None; Lynn C. Shaw, None; Tatiana Salazar, None; Colin Sumners, None; Julia Busik, None; Mohan Raizada, None; Maria Tikhonenko, None; Ulrike Steckelings, None; Maria B. Grant, None
  • Footnotes
    Support  NEI RO1 EY012601, NEI RO1 007739
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 2538. doi:
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      Sergio Li Calzi, Lynn C. Shaw, Tatiana Salazar, Colin Sumners, Julia Busik, Mohan Raizada, Maria Tikhonenko, Ulrike Steckelings, Maria B. Grant; Ang II Subtype 2 Receptor (AT2R) Activation By Compound 21 Reduces Endothelial Cell Migration in vitro and Neovascularization in the Oxygen-induced Retinopathy (OIR) Model. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2538.

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

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Abstract

Purpose: : In the Renin-Angiotensin System (RAS), angiotensin II (Ang II) binds to the Ang II subtype 1 receptor (AT1R) to stimulate inflammation whereas the Ang II subtype 2 receptor (AT2R) blocks the pro-inflammatory effect of AT1R and reduces inflammatory cytokine expression by vascular cells. The involvement of the RAS in diabetic retinopathy (DR) is suggested by increased angiotensin-converting enzyme (ACE) serum levels in diabetics; and by the reduction of retinal neovascularization in the OIR model in rats by treatment with inhibitors of the AT1R. In this study, we examined the effect of AT2R activation on retinal endothelial cell function in vitro and on neovascularization in the OIR model.

Methods: : Compound 21 (C21) was used as a highly selective AT2R agonist for both in vitro and in vivo studies. After removal from 75% oxygen on postnatal day 12, mouse pups were gavaged daily for five days with up to 0.06 mg/kg/day of C21. Mice were perfused with FITC-conjugated dextran on postnatal day 17 to visualize the retinal vasculature. One eye was taken for retinal flatmount analysis and the second eye was taken for retinal cross section analysis of pre-retinal neovascularization. Human retinal endothelial cells (HRECs) were used to determine the effect of C21 on migration to VEGF using a modified Boyden chamber assay.

Results: : Oral treatment of mouse pups with C21 reduced the amount of pre-retinal neovascularization by 26 ± 8% (p < 0.05) at a concentration of 0.06 mg/kg/day. Retinal flatmount analysis showed a significant reduction in vaso-obliteration in pups treated with C21 treatment. In vitro studies demonstrated that pretreatment of HREC with C21 inhibited their migration to VEGF in a dose dependent manner.

Conclusions: : C21 reduced pre-retinal neovascularization in the OIR model. C21 also reduced cell migration in HRECs. These results support the involvement of RAS in retinal neovascularization and in particular of the protective role of AT2R activation. C21 is a safe oral agent and may represent a viable therapeutic for treatment in DR and retinopathy of prematurity.

Keywords: receptors • retinal neovascularization • retinopathy of prematurity 
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