Antiangiogenic properties of BthMP, a P–I metalloproteinase from Bothrops moojeni snake venom by VEGF pathway in endothelial cells

• Published in: Biochemical and biophysical research communications Vol. 706; p. 149748
• Main Authors: Oliveira, Vinícius Queiroz, Santos, Luísa Carregosa, Teixeira, Samuel Cota, Correia, Thiago Macedo Lopes, Andrade, Leonardo Oliveira Silva Bastos, Gimenes, Sarah Natalie Cirilo, Colombini, Mônica, Marques, Lucas Miranda, Jiménez-Charris, Eliécer, Freitas-de-Sousa, Luciana Aparecida, Silva, Marcelo José Barbosa, Magalhães Gusmão, Amélia Cristina Mendes de, Ferro, Eloisa Amália Vieira, Clissa, Patricia Bianca, Melo Rodrigues, Veridiana de, Lopes, Daiana Silva
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.04.2024
• Subjects: Angiogenesis Inhibitors - pharmacology; Animals; Antiangiogenic effects and VEGF pathway; Bothrops - metabolism; Endothelial Cells - metabolism; Female; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Metalloproteases - metabolism; Metalloproteinase; Snake venom; Snake Venoms; Vascular Endothelial Growth Factor A - metabolism; Venomous Snakes; Snake venom; Metalloproteinase; Antiangiogenic effects and VEGF pathway
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2024.149748

Angiogenesis is a process that is controlled by a delicate combination of proangiogenic and antiangiogenic molecules and can be disrupted in various illnesses, including cancer. Non-cancerous diseases can also have an abnormal or insufficient vascular growth, inflammation and hypoxia, which exacerbate angiogenesis. These conditions include atherosclerosis, psoriasis, endometriosis, asthma, obesity and AIDS. Based on that, the present work assessed the in vitro and ex vivo antiangiogenic properties stemming from BthMP, a P–I metalloproteinase from Bothrops moojeni snake venom, via the VEGF pathway. BthMP at a concentration of 5 and 40 μg/mL showed no toxicity to endothelial cells (HUVEC) in the MTT assay and was not able to induce necrosis and colony proliferation. Interestingly, BthMP inhibited adhesion, migration and invasion of HUVECs in Matrigel and arrested in vitro angiogenesis by reducing the average number of nodules in toxin-treated cells by 9.6 and 17.32 at 5 and 40 μg/mL, respectively, and the number of tubules by 15.9 at 5 μg/mL and 21.6 at 40 μg/mL in a VEGF-dependent way, an essential proangiogenic property. Furthermore, BthMP inhibited the occurrence of the angiogenic process in an ex vivo aortic ring test by decreasing new vessel formation by 52% at 5 μg/mL and by 66% at 40 μg/mL and by increasing the expression of an antiangiogenic gene, SFLT-1, and decreasing the expression of the proangiogenic genes VEGFA and ANGPT-1. Finally, this toxin reduces the production of nitric oxide, a marker that promotes angiogenesis and VEGF modulation, and decreases the protein expression of VEGFA in the supernatant of the HUVEC culture by about 30 %. These results suggest that BthMP has a promising antiangiogenic property and proves to be a biotechnological mechanism for understanding the antiangiogenic responses induced by snake venom metalloproteinases, which could be applied to a variety of diseases that exhibit an imbalance of angiogenesis mechanisms. •BthMP inhibits adhesion, migration, and invasion of endothelial cells without cytotoxicity or cell necrosis.•BthMP promotes the inhibition of in vitro and ex vivo angiogenesis by modulating nitric oxide and VEGF.•BthMP upregulates the anti-angiogenic gene SFLT-1, while it downregulates the proangiogenic genes VEGFA and ANGPT-1.