April 2010
Volume 51, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2010
The Apelin/APJ Pathway in Retinal Angiogenesis
Author Affiliations & Notes
  • F. M. Recchia
    Ophthalmology and Visual Sciences, Retina Division,Vanderbilt Eye Institute, Nashville, Tennessee
  • L. Xu
    Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, Nashville, Tennessee
  • J. S. Penn
    Ophthalmology and Visual Sciences, Vanderbilt Eye Institute, Nashville, Tennessee
  • Footnotes
    Commercial Relationships  F.M. Recchia, None; L. Xu, None; J.S. Penn, None.
  • Footnotes
    Support  NIH (EY07533 and P30 EY08126); Unrestricted Departmental Grant from Research to Prevent Blindness, Inc.
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 28. doi:
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      F. M. Recchia, L. Xu, J. S. Penn; The Apelin/APJ Pathway in Retinal Angiogenesis. Invest. Ophthalmol. Vis. Sci. 2010;51(13):28.

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

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Abstract

Introduction: : Background/

Purpose: : Our laboratory has recently demonstrated increased retinal gene expression of apelin (apln), an angiogenic cytokine involved in cardiovascular development and fluid homeostasis, in two rodent models of oxygen-induced retinopathy (OIR). The present studies were undertaken to elucidate the role of apelin and its receptor, APJ, in retinal angiogenesis.

Methods: : Primary cultures of human retinal vascular endothelial cells (HRVECs) were used for in vitro experiments, and the rat model of OIR was used for in vivo experiments. Near-confluent HRVECs were treated for 24 hrs with either 10% FBS or serum-free medium, in the presence or absence of 2.5uM VEGF. In each of the four conditions, expression of the apelin and APJ genes were measured by qRT-PCR and concentration of apelin in the medium was measured by ELISA. Tube formation assays were performed in triplicate with HRVECs following addition of varying concentrations (2.5uM - 20uM) of recombinant apelin-12, and varying concentrations of two apelin inhibitors (apelin-13[F13A], a competitive antagonist, and siRNA against apln). Following induction of OIR by oxygen cycling, eyes of P15 rats were treated with an intravitreal injection of varying concentrations (1uM - 100uM) of apelin-13(F13A) or vehicle. Six days later, retinal flatmounts were stained with ADPase, and retinal vascular growth was assessed.

Results: : Expression of apelin and APJ mRNA in HRVECs, and secretion of apelin by HRVECs, were increased ≥ 2-fold following either stress with serum-free media or stimulation with VEGF. As little as 2.5 uM apelin significantly increased total tube formation (71.0 mm vs. 25.8 mm, P=0.01), an effect comparable to equimolar VEGF. Tube formation was reduced by 50% and 80% following treatment with apelin-13(F13A) and siRNA, respectively. In vivo, mean retinal avascular area was decreased (13.8mm2 vs 29.3mm2, p=0.001), and mean peripheral retinal neovascularization was significantly decreased (4.5 clock-hrs vs. 1.2 clock-hrs), in eyes treated with as little as 10 uM of apelin-13(F13A).

Conclusions: : The apelin/APJ pathway appears to be involved in retinal angiogenesis in vitro. Its effects may result from autocrine actions by retinal endothelial cells and through both VEGF-dependent and VEGF-independent mechanisms. Apelin inhibition reduces retinal NV in vivo, possibly by reducing peripheral avascularity. The apelin/APJ pathway may merit further study as a rational therapeutic target for anti-angiogenesis.

Keywords: retinal neovascularization 
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