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Victor Guaiquil, Zan Pan, Natalia Karagianni, Shima Fukuoka, Gemstonn Alegre, Mark I Rosenblatt; Vascular Endothelial Growth Factor-B selectively regenerates injured corneal nerves and restores both sensory and trophic functions.. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4694.
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To evaluate whether non-angiogenic VEGF-B can stimulate peripheral neuron growth and enhance the recovery of corneal innervation following injury
To evaluate the role of VEGF-B on promoting peripheral nerve regeneration we treated isolated trigeminal ganglia neuronal cells from Thy1-YFP mice with VEGF-B and inhibitors that regulate the VEGF-B pathway. The effect of VEGF-B on corneal nerve regeneration in vivo was evaluated via slow release of VEGF-B within the target tissue in Thy1-YFP mice (intrastromal pellet) or from an adjacent site (subconjunctival injection) in Vegf-b-/- and C57BL/6 mice. Regeneration of corneal nerve injury, induced by epithelium debridement, was evaluated by fluorescent microscopy and analyzed using Neurolida software. Epithelial wound healing and corneal angiogenesis was evaluated using slit lamp, and cornea sensation evaluated by von Frey Hairs. The expression of VEGF-B after cornea injury was determined by qPCR, ELISA and Western Blot. Human corneal limbal epithelial cell cultures were used in scratch assay to evaluate the regenerative role of VEGF-B in the epithelium
VEGF-B induces extensive dendrite elongation and branching in TG neurons that require VEGFR1 and neuropilin activation, but is independent of VEGFR2. VEGF-B is physiologically relevant as corneal injury increased expression of endogenous VEGF-B, and mice lacking VEGF-B have impaired corneal nerve regeneration. Addition of VEGF-B did not appear to affect existing innervation of the cornea. However, administration of VEGF-B to injured corneas, improves nerve regeneration, sensory recovery and trophic function in Vegf-b-/- and wild-type mice. VEGF-B did not induce an angiogenesis response in the treated injured corneas and failed to directly induce epithelial wound healing in culture
VEGF-B can selectively and potently enhance the regeneration of injured corneal nerves. This data identifies the VEGF-B signaling pathway as a potential neuroregenerative, but non-angiogenic target for inducing nerve repair in the setting of peripheral nervous system injury
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