Snake venom VEGF Vammin induces a highly efficient angiogenic response in skeletal muscle via VEGFR-2/NRP specific signaling

Abstract

Vascular Endothelial Growth Factors (VEGFs) are promising molecules for the treatment of ischemic diseases by pro-angiogenic therapy. Snake venom VEGFs are a novel subgroup with unique receptor binding profiles and as such are potential new therapeutic agents. We determined the ligand-receptor interactions, gene regulation and angiogenic properties of Vipera ammodytes venom VEGF, Vammin, and compared it to the canonical angiogenic factor VEGF-A to evaluate the use of Vammin for therapeutic angiogenesis. Vammin efficiently induced VEGFR-2 mediated proliferation and expression of genes associated with proliferation, migration and angiogenesis. VEGF-A165 and especially VEGF-A109 induced less pronounced effects. Vammin regulates a number of signaling pathways by inducing the expression of NR4A family nuclear receptors and regulators of calcium signaling and MAP kinase pathways. Interestingly, MARC1, which encodes an enzyme discovered to catalyze reduction of nitrate to NO, was identified as a novel VEGFR-2 regulated gene. In rabbit skeletal muscle adenoviral delivery of Vammin induced prominent angiogenic responses. Both the vector dose and the co-receptor binding of the ligand were critical parameters controlling the type of angiogenic response from sprouting angiogenesis to vessel enlargement. Vammin induced VEGFR-2/NRP-1 mediated signaling more effectively than VEGF-A, consequently it is a promising candidate for development of pro-angiogenic therapies.

Biogeographic venom variation in Russell’s viper (Daboia russelii) and the preclinical inefficacy of antivenom therapy in snakebite hotspots

“…Interestingly, snaclecs constituted nearly ~20% of the venom proteome of the Deccan Plateau (MP) population, whereas the Gangetic Plain (WB) and the Western Ghats (MH) populations contained only 5% and 2% of this toxin, respectively. While VEGF, a family of toxins responsible for inducing vascular permeability and lower blood pressure [ 39 , 40 ], was only identified in trace amounts in the other populations of D . russelii (<1%), it was found to constitute ~8% of the venom of the Deccan Plateau (MP) population ( S2 – S4 Tables).…”

Proteomic Investigations of Two Pakistani Naja Snake Venoms Species Unravel the Venom Complexity, Posttranslational Modifications, and Presence of Extracellular Vesicles

“…Studies have shown that different variants of snake venom VEGF induce angiogenesis and vascular permeability through different mechanisms [ 157 , 158 ]. Snake venom VEGF are potential candidates for therapeutic angiogenesis [ 159 ]. A low abundance of Kunitz type serine protease inhibitors (KSPI) was identified in the venom of both snakes.…”

Alternative mRNA Splicing in Three Venom Families Underlying a Possible Production of Divergent Venom Proteins of the Habu Snake, Protobothrops flavoviridis

“…For example, vammin and VR-1, isolated from the venoms of Vipera ammodytes and Daboia russelii , respectively, bind only kinase insert domain receptor (KDR) with high affinity but not to other VEGF receptors [19]. It is known that the C-terminal regions of VEGFs are one of the determinants for receptor specificities [20,21]. Yamazaki et al [18] has also reported that svVEGF of P. flavoviridis preferentially binds to Flt-1 rather than to KDR, unlike vammin and VR-1 [22].…”