Abstract
Vascular endothelial growth factor (VEGF)-B possesses the capacity of promoting injured peripheral nerve regeneration and restore their sensory and trophic functions. However, the contribution and mechanism of VEGF-B in diabetic peripheral neuropathy remains unclear. In the present study, we investigated the expression and role of VEGF-B in diabetic corneal neuropathy by using type 1 diabetic mice and cultured trigeminal ganglion (TG) neurons. Hyperglycemia attenuated the endogenous expression of VEGF-B in regenerated diabetic corneal epithelium, but not that of VEGF receptors in diabetic TG neurons and axons. Exogenous VEGF-B promoted diabetic corneal nerve fiber regeneration through the reactivation of PI-3K/Akt-GSK3β-mTOR signaling and the attenuation of neuronal mitochondria dysfunction via the VEGF receptor-1 and neuropilin-1. Moreover, VEGF-B improved corneal sensation and epithelial regeneration in both normal and diabetic mice, accompanied with the elevated corneal content of pigment epithelial-derived factor (PEDF). PEDF blockade partially abolished trophic function of VEGF-B in diabetic corneal re-innervation. In conclusion, hyperglycemia suppressed endogenous VEGF-B expression in regenerated corneal epithelium of diabetic mice, while exogenous VEGF-B promoted recovery of corneal innervations and trophic functions through reactivating PI-3K/Akt-GSK-3β-mTOR signaling, attenuating neuronal oxidative stress and elevating PEDF expression.
Highlights
Previous and our studies have confirmed that streptozotocin injection-induced type 1 diabetic mice assumed typical characteristics of diabetic corneal neuropathy, including impaired corneal nerve regeneration with concomitant attenuated corneal sensory and trophic functions[10,20,21]
To investigate the impairment of corneal innervations by hyperglycemia, streptozotocin- induced type 1 diabetic mouse model was used according to our previous reports[10,13]
Considering to the importance of oxidative stress in diabetic neuropathy, we further evaluated the regulations of Vascular endothelial growth factor (VEGF)-B on the intracellular reactive oxygen species (ROS) accumulation and mitochondrial dysfunction in cultured diabetic trigeminal ganglia (TG) neurons
Summary
Previous and our studies have confirmed that streptozotocin injection-induced type 1 diabetic mice assumed typical characteristics of diabetic corneal neuropathy, including impaired corneal nerve regeneration with concomitant attenuated corneal sensory and trophic functions[10,20,21]. Given the capacity of VEGF-B to restore the anatomic and function corneal innervations in normal mice, here we explored the contribution and mechanism of VEGF-B in diabetic corneal nerve fiber regeneration, corneal sensation and trophic function recovery by using type 1 diabetic mice and cultured trigeminal ganglion neurons
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