Ischemic neurons prevent vascular regeneration of neural tissue by secreting semaphorin 3A
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- Jean-Sébastien Joyal
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC;
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- Nicholas Sitaras
- Departments of Pediatrics, Ophthalmology, and Pharmacology, CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC;
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- François Binet
- Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, QC;
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- Jose Carlos Rivera
- Departments of Pediatrics, Ophthalmology, and Pharmacology, CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC;
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- Andreas Stahl
- Department of Ophthalmology, University of Freiburg, Freiburg, Germany;
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- Karine Zaniolo
- Departments of Pediatrics, Ophthalmology, and Pharmacology, CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC;
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- Zhuo Shao
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC;
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- Anna Polosa
- Department of Ophthalmology and Neurology-Neurosurgery, McGill Montreal Children's Hospital Research Institute, McGill University, Montreal, QC;
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- Tang Zhu
- Departments of Pediatrics, Ophthalmology, and Pharmacology, CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC;
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- David Hamel
- Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, QC;
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- Mikheil Djavari
- Department of Ophthalmology and Neurology-Neurosurgery, McGill Montreal Children's Hospital Research Institute, McGill University, Montreal, QC;
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- Dario Kunik
- Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, QC;
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- Jean-Claude Honoré
- Departments of Pediatrics, Ophthalmology, and Pharmacology, CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC;
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- Emilie Picard
- Departments of Pediatrics, Ophthalmology, and Pharmacology, CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC;
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- Alexandra Zabeida
- Departments of Pediatrics, Ophthalmology, and Pharmacology, CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC;
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- Daya R. Varma
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC;
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- Gilles Hickson
- Departments of Pediatrics, Ophthalmology, and Pharmacology, CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC;
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- Joseph Mancini
- Departments of Pediatrics, Ophthalmology, and Pharmacology, CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC;
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- Michael Klagsbrun
- Vascular Biology and
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- Santiago Costantino
- Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, QC;
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- Christian Beauséjour
- Departments of Pediatrics, Ophthalmology, and Pharmacology, CHU Sainte-Justine Research Center, University of Montreal, Montreal, QC;
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- Pierre Lachapelle
- Department of Ophthalmology and Neurology-Neurosurgery, McGill Montreal Children's Hospital Research Institute, McGill University, Montreal, QC;
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- Lois E. H. Smith
- Department of Ophthalmology, Children's Hospital Boston, Harvard Medical School, Boston, MA; and
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- Sylvain Chemtob
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC;
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- Przemyslaw Sapieha
- Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, QC;
Description
<jats:title>Abstract</jats:title> <jats:p>The failure of blood vessels to revascularize ischemic neural tissue represents a significant challenge for vascular biology. Examples include proliferative retinopathies (PRs) such as retinopathy of prematurity and proliferative diabetic retinopathy, which are the leading causes of blindness in children and working-age adults. PRs are characterized by initial microvascular degeneration, followed by a compensatory albeit pathologic hypervascularization mounted by the hypoxic retina attempting to reinstate metabolic equilibrium. Paradoxically, this secondary revascularization fails to grow into the most ischemic regions of the retina. Instead, the new vessels are misdirected toward the vitreous, suggesting that vasorepulsive forces operate in the avascular hypoxic retina. In the present study, we demonstrate that the neuronal guidance cue semaphorin 3A (Sema3A) is secreted by hypoxic neurons in the avascular retina in response to the proinflammatory cytokine IL-1β. Sema3A contributes to vascular decay and later forms a chemical barrier that repels neo-vessels toward the vitreous. Conversely, silencing Sema3A expression enhances normal vascular regeneration within the ischemic retina, thereby diminishing aberrant neovascularization and preserving neuroretinal function. Overcoming the chemical barrier (Sema3A) released by ischemic neurons accelerates the vascular regeneration of neural tissues, which restores metabolic supply and improves retinal function. Our findings may be applicable to other neurovascular ischemic conditions such as stroke.</jats:p>
Journal
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- Blood
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Blood 117 (22), 6024-6035, 2011-06-02
American Society of Hematology
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Details 詳細情報について
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- CRID
- 1362544419440510208
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- ISSN
- 15280020
- 00064971
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- Data Source
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- Crossref