Neurogenesis, Angiogenesis, and MRI Indices of Functional Recovery From Stroke

Chopp, Michael; Zhang, Zheng Gang; Jiang, Quan

doi:10.1161/01.str.0000250235.80253.e9

Cited by 185 publications

(141 citation statements)

References 81 publications

Supporting

Mentioning

136

Contrasting

Unclassified

Order By: Relevance

“…These results indicate greater impairment of vascular function in Nrf2 −/− retinas at P17 subjected to OIR. Restoration of blood supply via regrowth of functional vessels is crucial for the preservation of neural function in ischemic tissues (18,19). Given the vascular changes in Nrf2 −/− retinas, we also investigated neuronal function using electroretinography at P40 of OIR.…”

Section: Genetic Ablation Of Nrf2 Impedes Vascular Regeneration Andmentioning

confidence: 99%

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

Wei

Gong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

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.

show abstract

Section: Genetic Ablation Of Nrf2 Impedes Vascular Regeneration Andmentioning

confidence: 99%

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

Wei

Gong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Accelerated postischemic revascularization is associated with improved neural recovery. 37,38 OIR is associated with sustained depression in retinal function, 39 primarily in the inner retina (as reflected by the b-wave amplitude of the ERG). 5 To assess the functional benefits of inhibition of RGCderived Sema3A, we performed short-flash ERG analysis in 50-day-old OIR mice.…”

Section: Inhibition Of Rgc-derived Sema3a During Pr Preserves Neurorementioning

confidence: 99%

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

Joyal

Sitaras

Binet

et al. 2011

Blood

163

199

View full text Add to dashboard Cite

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) IntroductionProliferative retinopathies (PRs) are traditionally perceived as disorders limited to the microvasculature because of the characteristic profuse and deregulated growth of retinal vessels. 1 The mechanisms by which neovessels grow toward the vitreous and fail to revascularize ischemic zones are thought to result from high concentrations of proangiogenic factors such as VEGF in the vitreous of PR patients. However, if such an explanation were sufficient, retinal glial cells (astrocytes and Müller cells) 2 and neurons 3 that produce vast amounts of growth factors under hypoxic conditions should retain vessels on the retinal surface and ensure revascularization of the retina proper. It is, therefore, compelling to hypothesize the presence of a vasorepulsive force originating from the significantly hypoxic avascular retina that repels neovessels away from the vaso-obliterated retina and grows toward the vitreous.Neurovascular cross-talk shapes vascular development but has received limited attention in the pathology setting. In PRs, evidence points to an early decline in the function of ischemic regions of the neural retina, as shown by multifocal electroretinogram (mfERG). 4,5 Throughout the vaso-obliterative phase of retinopathy, the local retinal environment is hostile to both vasculature and neurons. 6 After blood vessel degeneration, neurons are metabolically starved and undergo several adaptive cellular changes to counter the ischemic state of the tissue. 3,6 If adequate vascular supply is not reinstated in time to salvage deprived neurons, it is conceivable that these severely hypoxic cells may mount a repulsive front in an attempt to shunt metabolic resources away from the perishing ischemic tissue toward less affected regions of the retina. In the process, excessive production of VEGF 7 induces exaggerated neovascularization at the periphery of the ischemic and repulsive zones into the pre-retinal region (normally devoid of vasculature), because reestablishing a vascular network to neurons that are unsalvageable would be wasteful.Given their established role in influencing endothelial cell (EC) behavior, classic neuronal guidance cues may ...

show abstract

“…The most well documented example of these endothelial-brain interactions comprise the neurovascular niche. It is now accepted that cell-cell signaling between cerebral endothelium and neuronal precursor cells helps mediate and sustain pockets of ongoing neurogenesis and angiogenesis in adult brain (Iadecola, 2004;Greenberg and Jin, 2005;Chopp et al, 2007;Zacchigna et al, 2008;Zlokovic, 2008).…”

Section: Introductionmentioning

confidence: 99%

An Oligovascular Niche: Cerebral Endothelial Cells Promote the Survival and Proliferation of Oligodendrocyte Precursor Cells

Arai

Lo²

2009

J. Neurosci.

222

230

View full text Add to dashboard Cite

We show that cerebral endothelial cells secrete trophic factors that support the survival and proliferation of rat oligodendrocyte precursor cells (OPCs). This OPC-supportive phenomenon was mediated by Akt and Src signaling pathways. Noncytotoxic levels of oxidative stress downregulate trophic factor production and disrupt the ability of cerebral endothelial cells to support OPCs. These data suggest that a novel oligovascular niche may be important for sustaining oligodendrocyte renewal and homeostasis in mammalian brain.

show abstract

Neurogenesis, Angiogenesis, and MRI Indices of Functional Recovery From Stroke

Cited by 185 publications

References 81 publications

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

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

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

An Oligovascular Niche: Cerebral Endothelial Cells Promote the Survival and Proliferation of Oligodendrocyte Precursor Cells

Contact Info

Product

Resources

About