Nerve Growth Factor-Induced Protection of Brain Capillary Endothelial Cells Exposed to Oxygen–Glucose Deprivation Involves Attenuation of Erk Phosphorylation

Abstract

Nerve growth factor (NGF) was recently characterized as an angiogenic factor inducing proliferation, migration, and capillary sprouting in endothelial cells (ECs) of different vascular beds. While NGF neuroprotective effects on neurons were described, its survival-inducing effects on brain capillary ECs were not yet addressed. Using a model of oxygen–glucose deprivation (OGD) followed by reoxygenation, we demonstrated that NGF conferred protection in brain capillary ECs. These cells express TrkA and p75NTR receptors and respond to NGF by stimulation of Erk1/2 phosphorylation and stimulation of proliferation and migration. The NGF protective effect was dose-dependent, inhibited by NGF/TrkA antagonist, K252a, and required presence of NGF during both OGD and reoxygenation phases while the major protective effect was related to decreased cell death during the reoxygenation phase. A causal relationship was found between NGF-induced protection and attenuation of OGD-induced Erk1/2 phosphorylation, supporting the death-promoting role of insult-induced Erk1/2 phosphorylation in the brain capillary ECs. These results emphasize the importance of NGF in the process of EC survival in response to ischemic injury and suggest fine-tuning regulation of Erk1/2 phosphorylation, extending the neuroprotective impact of NGF from sympathetic neuroendocrine cells to brain capillary ECs as the other element in the neurovascular tandem.

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Acknowledgments

This research was supported in part by a grant-in-aid form the Stein Family Foundations (PL and PIL). PL is affiliated and partially supported by the David R. Bloom Center for Pharmacy and the Dr. Adolf and Klara Brettler Center for Research in Molecular Pharmacology and Therapeutics at The Hebrew University of Jerusalem, Israel. SL is supported by "Eshkol fellowship" from the Israeli Ministry of Science, Culture and Sport. The authors would like to acknowledge the help of Mr. Yoav Wagenstein for technical assistance and Mrs. Zehava Cohen for graphics design.

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Correspondence to Philip Lazarovici.

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This study is part of the PhD thesis of Shimon Lecht to be submitted to The Hebrew University of Jerusalem.

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Lecht, S., Arien-Zakay, H., Marcinkiewicz, C. et al. Nerve Growth Factor-Induced Protection of Brain Capillary Endothelial Cells Exposed to Oxygen–Glucose Deprivation Involves Attenuation of Erk Phosphorylation. J Mol Neurosci 41, 183–192 (2010). https://doi.org/10.1007/s12031-009-9318-0

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Keywords

  • Nerve growth factor
  • Erk1/2
  • Oxygen–glucose deprivation and reoxygenation
  • Protection
  • Endothelial cells