title: Ischemic neurons prevent vascular regeneration of neural tissue by secreting semaphorin 3A.
abstract: 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.
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Joyal
authors.forename: Nicholas
authors.initials: N
authors.lastname: Sitaras
authors.forename: François
authors.initials: F
authors.lastname: Binet
authors.forename: Jose Carlos
authors.initials: JC
authors.lastname: Rivera
authors.forename: Andreas
authors.initials: A
authors.lastname: Stahl
authors.forename: Karine
authors.initials: K
authors.lastname: Zaniolo
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Shao
authors.forename: Anna
authors.initials: A
authors.lastname: Polosa
authors.forename: Tang
authors.initials: T
authors.lastname: Zhu
authors.forename: David
authors.initials: D
authors.lastname: Hamel
authors.forename: Mikheil
authors.initials: M
authors.lastname: Djavari
authors.forename: Dario
authors.initials: D
authors.lastname: Kunik
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Honoré
authors.forename: Emilie
authors.initials: E
authors.lastname: Picard
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zabeida
authors.forename: Daya R
authors.initials: DR
authors.lastname: Varma
authors.forename: Gilles
authors.initials: G
authors.lastname: Hickson
authors.forename: Joseph
authors.initials: J
authors.lastname: Mancini
authors.forename: Michael
authors.initials: M
authors.lastname: Klagsbrun
authors.forename: Santiago
authors.initials: S
authors.lastname: Costantino
authors.forename: Christian
authors.initials: C
authors.lastname: Beauséjour
authors.forename: Pierre
authors.initials: P
authors.lastname: Lachapelle
authors.forename: Lois E H
authors.initials: LE
authors.lastname: Smith
authors.forename: Sylvain
authors.initials: S
authors.lastname: Chemtob
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Sapieha
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007124:Immunoenzyme Techniques; D053583:Interleukin-1beta / Q000494:pharmacology; D007511:Ischemia / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010100:Oxygen / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D012038:Regeneration; D012164:Retinal Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism; D015861:Retinal Neovascularization; D020133:Reverse Transcriptase Polymerase Chain Reaction; D040121:Semaphorin-3A / Q000502:physiology*
chemical_list: D053583:Interleukin-1beta; D012333:RNA, Messenger; D040121:Semaphorin-3A; D010100:Oxygen