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Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury.

ABSTRACT: Vascular endothelial growth factor-A (VEGF-A) has recently been recognized as an important neuroprotectant in the central nervous system. Given its position as an anti-angiogenic target in the treatment of human diseases, understanding the extent of VEGF's role in neural cell survival is paramount. Here, we used a model of ischemia-reperfusion injury and found that VEGF-A exposure resulted in a dose-dependent reduction in retinal neuron apoptosis. Although mechanistic studies suggested that VEGF-A-induced volumetric blood flow to the retina may be partially responsible for the neuroprotection, ex vivo retinal culture demonstrated a direct neuroprotective effect for VEGF-A. VEGF receptor-2 (VEGFR2) expression was detected in several neuronal cell layers of the retina, and functional analyses showed that VEGFR2 was involved in retinal neuroprotection. VEGF-A was also shown to be involved in the adaptive response to retinal ischemia. Ischemic preconditioning 24 hours before ischemia-reperfusion injury increased VEGF-A levels and substantially decreased the number of apoptotic retinal cells. The protective effect of ischemic preconditioning was reversed after VEGF-A inhibition. Finally, chronic inhibition of VEGF-A function in normal adult animals led to a significant loss of retinal ganglion cells yet had no observable effect on several vascular parameters. These findings have implications for both neural pathologies and ocular vascular diseases, such as diabetic retinopathy and age-related macular degeneration.

SUBMITTER: Nishijima K

PROVIDER: S-EPMC1941589 | biostudies-literature | 2007 Jul

REPOSITORIES: biostudies-literature

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Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury.

Nishijima Kazuaki K Ng Yin-Shan YS Zhong Lichun L Bradley John J Schubert William W Jo Nobuo N Akita Jo J Samuelsson Steven J SJ Robinson Gregory S GS Adamis Anthony P AP Shima David T DT

The American journal of pathology 20070701 1

Vascular endothelial growth factor-A (VEGF-A) has recently been recognized as an important neuroprotectant in the central nervous system. Given its position as an anti-angiogenic target in the treatment of human diseases, understanding the extent of VEGF's role in neural cell survival is paramount. Here, we used a model of ischemia-reperfusion injury and found that VEGF-A exposure resulted in a dose-dependent reduction in retinal neuron apoptosis. Although mechanistic studies suggested that VEGF ...[more]

PMID: 17591953

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Project description: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.

Dataset Information

Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury.

Publications

Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury.

Similar Datasets

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