Ischemic neurons prevent vascular regeneration of neural tissue by secreting semaphorin 3A.

JOYAL JS,; SITARAS N,; RIVERA JC,; STAHL A,; ZANIOLO K,; SHAO Z,; POLOSA A,; ZHU T,; HAMEL D,; DJAVARI M,; KUNIK D,; HONORÉ JC,; PICARD E,; ZABEIDA A,; VARMA DR,; HICKSON G,; MANCINI J,; KLAGSBRUN M,; COSTANTINO S,; BEAUSÉJOUR C,; LACHAPELLE P,; SMITH LE, CHEMTOB S,; SAPIEHA P. D

BLOOD, THE JOURNAL OF THE AMERICAN SOCIETY OF HEMATOLOGY - ONLINE

Blood

Lugar: Washington; Año: 2011

1528-0020

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 pathological hyper-vascularization 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 towards the vitreous, suggesting that vaso-repulsive forces operate in the avascular hypoxic retina. Here we demonstrate that the neuronal guidance cue Semaphorin3A (Sema3A) is secreted by hypoxicneurons in the avascular retina in response to the pro-inflammatory cytokine Interleukin-1β. Sema3A contributes to vascular decay and later forms a chemical barrier that repels neo-vessels towards the vitreous. Conversely, silencing Sema3A expression enhances normalvascular regeneration within the ischemic retina, thereby diminishing aberrant neovascularization and preserving neuro-retinal 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; findings may be applicable to other neurovascular ischemic conditions such as stroke.