A VEGFB-Based Peptidomimetic Inhibits VEGFR2-Mediated PI3K/Akt/mTOR and PLCγ/ERK Signaling and Elicits Apoptotic, Antiangiogenic, and Antitumor Activities

• DOI: 10.20944/preprints202305.0844.v1
• Publication Date: 2023-05-12T01:11:12Z
• Authors: Mohadeseh Namjoo; Hossein Ghafoori; Elham Assareh; Amir Reza Aref; Ebrahim Mostafavi; Ali Hamrahi Mohsen; Saeed Balalaei; Sylvain Broussy; S. Mohsen Asghari
• Keywords: Peptidomimetic

Vascular endothelial growth factor receptor 2 (VEGFR2) mediates VEGFA signaling mainly through the PI3K/AKT/mTOR and PLCγ/ERK1/2 pathways. Here we unveil a peptidomimetic (VGB3) based on interaction between VEGFB VEGFR1 that unexpectedly binds neutralizes VEGFR2. Investigation of cyclic linear structures VGB3 using binding cell proliferation assays, molecular docking, evaluation antiangiogenic antitumor activities in 4T1 mouse mammary tumor model showed loop formation is essential for peptide functionality. inhibited tubulogenesis human umbilical vein cells (HUVECs), accounting abrogation VEGFR2, p-VEGFR2 and, subsequently, In cells, proliferation, VEGFR2 expression phosphorylation, pathway, FAK/Paxillin, epithelial-to-mesenchymal transition cascade. The apoptotic effects HUVE were inferred from annexin-PI TUNEL staining activation P53, caspase-3, caspase-7, PARP1, which mechanistically occurred intrinsic pathway mediated by Bcl2 family members, Cytochrome c, Apaf-1 caspase-9, extrinsic via death receptors caspase-8. These data indicate regions shared VEGF members may be important developing novel pan-VEGFR inhibitors are highly relevant pathogenesis angiogenesis-related diseases.