Journal Article

VEGF-B selectively regenerates injured peripheral neurons and restores sensory and trophic functions

Guaiquil, Victor H., Fukuoka, Shima, Alegre, Gemstonn, Pan, Zan, Karagianni, Natalia, Rosenblatt, Mark I.

2014

Overview

Significance Peripheral nerve injury is a major neurological disorder that can cause multiple motor and sensory disturbances. In this study we found that VEGF-B can be used as a previously unidentified therapeutic for treating peripheral nerve injury. We demonstrated that VEGF-B stimulated nerve regeneration and enhanced the recovery of both tissue sensation and the ability of nerves to enhance healing of innervated tissue. The physiologic relevance of VEGF-B is demonstrated by our findings showing that mice lacking VEGF-B have impaired nerve regeneration and that nerve injury resulted in increased endogenous expression of VEGF-B. We discover that VEGF-B induces strong elongation and branching of neurons and requires specific transmembrane receptors as well as activation of a complex intracellular signaling. VEGF-B primarily provides neuroprotection and improves survival in CNS-derived neurons. However, its actions on the peripheral nervous system have been less characterized. We examined whether VEGF-B mediates peripheral nerve repair. We found that VEGF-B induced extensive neurite growth and branching in trigeminal ganglia neurons in a manner that required selective activation of transmembrane receptors and was distinct from VEGF-A–induced neuronal growth. VEGF-B–induced neurite elongation required PI3K and Notch signaling. In vivo, VEGF-B is required for normal nerve regeneration: mice lacking VEGF-B showed impaired nerve repair with concomitant impaired trophic function. VEGF-B treatment increased nerve regeneration, sensation recovery, and trophic functions of injured corneal peripheral nerves in VEGF-B–deficient and wild-type animals, without affecting uninjured nerves. These selective effects of VEGF-B on injured nerves and its lack of angiogenic activity makes VEGF-B a suitable therapeutic target to treat nerve injury.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Animals / Biological Sciences / Blotting, Western / Cell growth / Cell Proliferation - drug effects / Cell Survival - drug effects / Cell Survival - genetics / Cells, Cultured / Cornea / Cornea - drug effects / Cornea - innervation / Cornea - physiopathology / Debridement / Epithelium / Mice / Mice, Inbred C57BL / Mice, Knockout / Mice, Transgenic / Microscopy, Fluorescence / Nerve regeneration / Nerve Regeneration - drug effects / Nerve Regeneration - genetics / Nerve Regeneration - physiology / nerve tissue / Nerves / Nervous system / nervous system diseases / Neurites / Neurites - drug effects / Neurites - physiology / Neurons / Neurons - drug effects / Neurons - metabolism / Neurons - physiology / Peripheral Nerve Injuries - genetics / Peripheral Nerve Injuries - physiopathology / Peripheral nerves / Peripheral Nerves - drug effects / Peripheral Nerves - pathology / Peripheral Nerves - physiopathology / Phosphatidylinositol 3-Kinases - metabolism / Proto-Oncogene Proteins c-akt - metabolism / receptors / Receptors, Notch - metabolism / Rodents / Sensation / Signal Transduction - drug effects / Trigeminal Ganglion - cytology / Vascular endothelial growth factor / vascular endothelial growth factor B / Vascular Endothelial Growth Factor B - genetics / Vascular Endothelial Growth Factor B - metabolism / Vascular Endothelial Growth Factor B - pharmacology / Vascular Endothelial Growth Factor Receptor-1 - metabolism