Nrf2 in ischemic neurons promotes retinal vascular regeneration through regulation of semaphorin 6A

Abstract

Delayed revascularization of ischemic neural tissue is a major impediment to preservation of function in central nervous system (CNS) diseases including stroke and ischemic retinopathies. Therapeutic strategies allowing rapid revascularization are greatly needed to reduce ischemia-induced cellular damage and suppress harmful pathologic neovascularization. However, key mechanisms governing vascular recovery in ischemic CNS, including regulatory molecules governing the transition from tissue injury to tissue repair, are largely unknown. NF-E2-related factor 2 (Nrf2) is a major stress-response transcription factor well known for its cell-intrinsic cytoprotective function. However, its role in cell–cell crosstalk is less appreciated. Here we report that Nrf2 is highly activated in ischemic retina and promotes revascularization by modulating neurons in their paracrine regulation of endothelial cells. Global Nrf2 deficiency strongly suppresses retinal revascularization and increases pathologic neovascularization in a mouse model of ischemic retinopathy. Conditional knockout studies demonstrate a major role for neuronal Nrf2 in vascular regrowth into avascular retina. Deletion of neuronal Nrf2 results in semaphorin 6A (Sema6A) induction in hypoxic/ischemic retinal ganglion cells in a hypoxia-inducible factor-1 alpha (HIF-1α)-dependent fashion. Sema6A expression increases in avascular inner retina and colocalizes with Nrf2 in human fetal eyes. Extracellular Sema6A leads to dose-dependent suppression of the migratory phenotype of endothelial cells through activation of Notch signaling. Lentiviral-mediated delivery of Sema6A small hairpin RNA (shRNA) abrogates the defective retinal revascularization in Nrf2-deficient mice. Importantly, pharmacologic Nrf2 activation promotes reparative angiogenesis and suppresses pathologic neovascularization. Our findings reveal a unique function of Nrf2 in reprogramming ischemic tissue toward neurovascular repair via Sema6A regulation, providing a potential therapeutic strategy for ischemic retinal and CNS diseases.

Nrf2 Activation Induced by Sirt1 Ameliorates Acute Lung Injury After Intestinal Ischemia/Reperfusion Through NOX4-Mediated Gene Regulation

“…Nrf2 has been implicated in regulating ischemic angiogenesis in a number of diseases such as cardiovascular diseases [20, 21] and ischemic retinopathies [11]. Nrf2 is also believed to protect a number of organs against IIR injury [22] including the lungs [23].…”

“…Under basal conditions Nrf2 is bound to KEAP1 (Kelch-like ECH-associated protein 1) in the cytosol, however, on exposure to oxidative stress, Nrf2 disassociates from KEAP1 and translocates into the nucleus where it enhances the transcription of target antioxidant genes through AREs, thereby increasing cytoprotection [9]. Nrf2 has also been implicated in regulating ischemic angiogenesis in the retina and other tissue beds [10, 11]. Nrf2 is thought to confer a protective role in lung damage associated with oxidative stress as inflammation and injury are increased when it is deficient [12].…”

RS9, a novel Nrf2 activator, attenuates light‐induced death of cells of photoreceptor cells and Müller glia cells

“…Nrf2 also promotes retinal vascular regeneration in ischemic neurons (Wei et al . ), and deficiency of Nrf2 produced ocular pathology similar to human AMD (Zhao et al . ).…”

miR‐30a‐5p inhibition promotes interaction of Fas+ endothelial cells and FasL+ microglia to decrease pathological neovascularization and promote physiological angiogenesis

“…p-values were calculated using one-way ANOVA with Bonferroni correction, *p < .05, **p < .001, ***p < .0001 pathologic NV and promoting physiologic revascularization. Protection of retinal neurons has also been shown to promote revascularization in the OIR model (Wei et al, 2015). Our ISH data shows that miR-30a is widely expressed across the retina, suggesting it may also be expressed by retinal neurons.…”

“…The work presented here shows that miR‐30a inhibition has a profound effect on microglia and endothelial cells, thus suppressing pathologic NV and promoting physiologic revascularization. Protection of retinal neurons has also been shown to promote revascularization in the OIR model (Wei et al, ). Our ISH data shows that miR‐30a is widely expressed across the retina, suggesting it may also be expressed by retinal neurons.…”