Simetryn induces arteriovenous malformations in zebrafish embryos through activation of Erk signaling.

Abstract

Arteriovenous malformations (AVMs) represent a congenital, high-flow vascular anomaly characterized by direct, aberrant connections between arteries and veins. This pathology leads to diverse clinical manifestations including skin discoloration, pain, ulceration, hemorrhage, and disfigurement. While most current animal AVM models rely on genetic engineering, chemically induced models remain scarce. In this study, we report that simetryn, a triazine herbicide, can induce AVM-like phenotypes in zebrafish embryos. Exposure to simetryn caused aberrant vascular development and erythrocyte accumulation within the caudal vascular plexus. We also observed a reduction in caudal lymphatic vessels and disrupted of cerebral vasculature. In the caudal vascular plexus, cellular proliferation was decreased while apoptosis was increased. Mechanistically, simetryn upregulated levels of phosphorylated Erk (p-Erk),. Notably, these AVM-like phenotypes were ameliorated by co-treatment with trametinib, a MEK inhibitor acting upstream of Erk. Our findings establish a novel, drug-induced zebrafish model of AVMs, which holds promise for facilitating high-throughput drug screening and advance the study of AVM pathogenesis.