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Neurotrophic effects of vascular endothelial growth factor B and novel mimetic peptides on neurons from the central nervous system.

Oksana Dmytriyeva,Amaia de Diego Ajenjo,Kathrine Lundø,Henrik Hertz,K. K. Rasmussen,A. Christiansen,J. Klingelhofer,Alexander L. Nielsen,Jan Hoeber,E. Kozlova,D. Woldbye,S. Pankratova

Published 2020 in ACS Chemical Neuroscience

ABSTRACT

Vascular endothelial growth factor B (VEGFB) is a pleiotropic trophic factor which, in contrast to the closely related VEGFA, is known to have a limited effect on angiogenesis. VEGFB improves survival in various tissues including the nervous system, where the effect was observed mainly for peripheral neurons. The neurotrophic effect of VEGFB on central nervous system neurons has been less investigated. Here we demonstrated that VEGFB promotes neurite outgrowth from primary cerebellar granule, hippocampal and retinal neurons in vitro. VEGFB protected hippocampal and retinal neurons from both oxidative stress and glutamate-induced neuronal death. The VEGF receptor 1 (VEGFR1) is required for VEGFB-induced neurotrophic and neuroprotective effects. Using a structure-based approach, we designed short peptides, termed Vefins1-7, mimicking the binding interface of VEGFB to VEGFR1. Vefins were analyzed for their secondary structure and binding to VEGF receptors and compared with previously described peptides derived from VEGFA, another ligand of VEGFR1. We show that Vefins have neurotrophic and neuroprotective effects on primary hippocampal, cerebellar granule and retinal neurons in vitro with potencies comparable to VEGFB. Similar to VEGFB, Vefins were not mitogenic for MCF-7 cancer cells. Furthermore, one of the peptides, Vefin7, dose-dependently even inhibited the proliferation of MCF-7 cells in vitro. Unraveling the neurotrophic and neuroprotective potentials of VEGFB, the only non-angiogenic factor of the VEGF family, is promising for the development of neuroprotective peptide-based therapies.

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