April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
Ischemic Neurons Prevent Vascular Regeneration Of Neural Tissue By Secreting Semaphorin 3A
Author Affiliations & Notes
  • Jean-Sebastien Joyal
    Ophthalmology, Harvard Univ/Childrens Hospital, Boston, Massachusetts
  • Nicholas Sitaras
    Pediatrics & Pharmacology, Research Ctr/Hosp Ste Justine, Montreal, Quebec, Canada
  • Francois Binet
    Pediatrics & Pharmacology, Research Ctr/Hosp Ste Justine, Montreal, Quebec, Canada
  • Karine Zaniolo
    Pediatrics & Pharmacology, Research Ctr/Hosp Ste Justine, Montreal, Quebec, Canada
  • Andreas Stahl
    Ophthalmology, Harvard Univ/Childrens Hospital, Boston, Massachusetts
  • Pierre Lachapelle
    Ophthalmology, McGill U-Montreal Childrens Hosp, Montreal, Quebec, Canada
  • Lois E. Smith
    Ophthalmology, Harvard Univ/Childrens Hospital, Boston, Massachusetts
  • Sylvain Chemtob
    Pediatrics & Pharmacology, Research Ctr/Hosp Ste Justine, Montreal, Quebec, Canada
  • Przemyslaw Mike Sapieha
    Ophthalmology, Universite de Montreal, Montreal, Quebec, Canada
  • Footnotes
    Commercial Relationships  Jean-Sebastien Joyal, None; Nicholas Sitaras, None; Francois Binet, None; Karine Zaniolo, None; Andreas Stahl, None; Pierre Lachapelle, None; Lois E. Smith, None; Sylvain Chemtob, None; Przemyslaw Mike Sapieha, None
  • Footnotes
    Support  This stuy was supported by grants from the Canadian Intitutes of Health Research (CIHR), the March of Dimes Birth Defects Foundation, the Fonds de la Recherche en Sante du Quebec.
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 3171. doi:
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      Jean-Sebastien Joyal, Nicholas Sitaras, Francois Binet, Karine Zaniolo, Andreas Stahl, Pierre Lachapelle, Lois E. Smith, Sylvain Chemtob, Przemyslaw Mike Sapieha; Ischemic Neurons Prevent Vascular Regeneration Of Neural Tissue By Secreting Semaphorin 3A. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3171.

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

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Abstract

Purpose: : The failure of blood vessels to revascularize ischemic neural tissue represents a significant challenge for vascular biology. We have previously demonstrated that the energy requirement of neurons triggers retinal neovascularization. Paradoxically, physiological revascularization is impeded in ischemic retinopathies, where blood vessels grow towards the vitreous body and fail to enter ischemic regions of the retina. In light of the anatomic coupling between neurons and vessels, shared guidance mechanisms have been inferred. Here we demonstrate that the neuronal repulsion cue Semaphorin3A (Sema3A) is secreted by hypoxic neurons in the avascular retina. Sema3A contributes to vascular decay and later forms a chemical barrier that repels neo-vessels towards the vitreous.

Methods: : The expression of Sema3A and their receptor Neuropilin-1 was assessed by Western blot, immnunohistochemistry and laser capture micro-dissection (LCM) with quantitative real time PCR. The extent of retinal vaso-obliteration (VO) and neovascularization (NV) was determined in a mouse model of oxygen-induce retinopathy following Sema3A knockdown in retinal ganglion cells (RGCs). Repulsion of vessels by Sema3A was confirmed ex vivo using ECs and aortic ring sprouting assays. Retinal function was assayed by full field electroretinograms (ERGs).

Results: : Following OIR, ischemic RGCs in the avascular zone produce Sema3A in response to Interleukin-1b, while their receptor Neuropilin-1 is predominantly found on neo-vascular tufts. Silencing Sema3A expression during OIR increases tip cell formation and enhances the rate of physiologic revascularization of the ischemic retina (by more then 50%). The total area of VO is similarly reduced. Inhibition of Sema3A production effectively curtails pathological pre-retinal NV (by ~50%). Consistent with a role in vascular repulsion, neo-vessels persistently avoid Sema3A rich zones in a 3D model of vascular sprouting. These effects of Sema3A knockdown translate into substantial gains in visual function as determined by ERGs.

Conclusions: : Overcoming the chemical barrier (Sema3A) released by ischemic neurons accelerates the vascular regeneration of neural tissues, which restores metabolic supply and improves retinal function.

Keywords: retinal neovascularization • ganglion cells • proliferative vitreoretinopathy 
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