Inhibition of Vascular Endothelial Growth Factor Receptor 2 Exacerbates Loss of Lower Motor Neurons and Axons during Experimental Autoimmune Encephalomyelitis.

Sarrabeth Stone,Xiaosha Pang,Milos Stanojlovic,Yifeng Lin,Robert Shin Fujinami,Marija Cvetanovic,Wensheng Lin

doi:10.1371/journal.pone.0160158

Sarrabeth Stone, Xiaosha Pang + Show 5 more

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https://doi.org/10.1371/journal.pone.0160158

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Journal: PloS one	Publication Date: Jul 28, 2016
Citations: 17	License type: CC BY 4.0

Affiliation: University of Minnesota

Abstract

Multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are inflammatory demyelinating and neurodegenerative diseases in the central nervous system (CNS). It is believed that MS and EAE are initiated by autoreactive T lymphocytes that recognize myelin antigens; however, the mechanisms responsible for neurodegeneration in these diseases remain elusive. Data indicate that vascular endothelial growth factor A (VEGF-A) plays a role in the development of MS and EAE. Interestingly, VEGF-A is regarded as a neurotrophic factor in the CNS that promotes neuron survival and neurogenesis in various neurodegenerative diseases by activating VEGF receptor 2 (VEGFR2). In this study, we sought to explore the role of the VEGF-A/VEGFR2 signaling in neurodegeneration in MS and EAE. We showed that the expression of VEGF-A was decreased in the spinal cord during EAE and that VEGFR2 was activated in lower motor neurons in the spinal cord of EAE mice. Interestingly, we found that treatment with SU5416, a selective VEGFR2 inhibitor, starting after the onset of EAE clinical symptoms exacerbated lower motor neuron loss and axon loss in the lumbar spinal cord of mice undergoing EAE, but did not alter Purkinje neuron loss in the cerebellum or upper motor neuron loss in the cerebral cortex. Moreover, SU5416 treatment had a minimal effect on EAE clinical symptoms as well as inflammation, demyelination, and oligodendrocyte loss in the lumbar spinal cord. These results imply the protective effects of the VEGF-A/VEGFR2 signaling on lower motor neurons and axons in the spinal cord in MS and EAE.

Highlights

Multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are T-cell-mediated autoimmune diseases of the central nervous system (CNS), characterized by inflammatory demyelinated lesions in the white matter [1, 2]
Our previous studies showed that C57BL/6J mice immunized with MOG 35–55 peptide develop typical EAE disease course, the mice developed neurological signs of disease starting at approximately post-immunization day (PID) 12, reached the peak of disease around PID 19, and started recovering from EAE at approximately PID 22 [23,24,25,26]
Recent studies showed that Vascular endothelial growth factor A (VEGF-A) plays an important role in the CNS under normal and disease conditions [11, 20]

Summary

Introduction

Multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are T-cell-mediated autoimmune diseases of the central nervous system (CNS), characterized by inflammatory demyelinated lesions in the white matter [1, 2]. The hallmarks of the demyelinated lesions in MS and EAE include inflammation, demyelination, oligodendrocyte loss, and axon degeneration. Significant neuron loss has been observed in the CNS gray matter of animals undergoing EAE, including the spinal cord, cerebral cortex, cerebellum, and hippocampus [5,6,7,8]. The current predominant view is that inflammation is responsible for axon degeneration and neuron loss in MS and EAE [9, 10], the molecular mechanisms responsible for neurodegeneration in these diseases remain largely unknown. The role of the VEGF-A/VEGFR2 signaling in neurodegeneration in MS and EAE remains unexplored

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