Peptides Derived from Vascular Endothelial Growth Factor B Show Potent Binding to Neuropilin‐1

Abstract

Vascular endothelial growth factors (VEGFs) regulate significant pathways in angiogenesis, myocardial and neuronal protection, metabolism, and cancer progression. The VEGF-B growth factor is involved in cell survival, anti-apoptotic and antioxidant mechanisms, through binding to VEGF receptor 1 and neuropilin-1 (NRP1). We employed surface plasmon resonance technology and X-ray crystallography to analyse the molecular basis of the interaction between VEGF-B and the b1 domain of NRP1, and developed VEGF-B C-terminus derived peptides to be used as chemical tools for studying VEGF-B -NRP1 related pathways. Peptide lipidation was used as a means to stabilise the peptides. VEGF-B-derived peptides containing a C-terminal arginine show potent binding to NRP1-b1. Peptide lipidation increased binding residence time and improved plasma stability. A crystal structure of a peptide with NRP1 demonstrated that VEGF-B peptides bind at the canonical C-terminal arginine binding site. VEGF-B C-terminus imparts higher affinity for NRP1 than the corresponding VEGF-A 165 region. This tight binding may impact on the activity and selectivity of the fulllength protein. The VEGF-B 167 derived peptides were more effective than VEGF-A 165 peptides in blocking functional phosphorylation events. Blockers of VEGF-B function have potential applications in diabetes and non-alcoholic fatty liver disease.

Determination of Vascular Endothelial Growth Factor-B Concentrations in Aqueous Humor and Plasma of Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy Patients Before and After Anti-VEGF Therapy

“…Therefore there was an urgent need to fully explore the functional roles of VEGF-B. Through analyzing the angiogenic role of VEGF-B under normal and pathologic circumstances, contrasting results were obtained with some studies indicating that VEGF-B was angiogenic and others the opposite [13,20,21]. Mesquita et al [21] stated that VEGF-B had no definite angiogenic effect and hence it did not promote vessel formation or sprouting, whereas its transgenic overexpression minimally increased vasculature, and overexpression of VEGF-B did not lead to any side effects.…”

“…Moreover, previous studies highlighted that an essential feature of VEGF-B was to protect retinal cells against apoptosis caused by anti-VEGF-A antagonists [10,11]. Furthermore, VEGF-B was identified to have antioxidant function mediated by VEGFR1 [12,13]. VEGFB gene deletion in mice led to degeneration of retina, and supplementation with VEGF-B in the retinitis pigmentosa model rescued retinal cells from death.…”