Bisphenol S and tetrabromobisphenol S induce the sprouting angiogenesis and ectopic sprouting vessel dysfunction via disturbing endothelial cell-cell adherens junction in zebrafish

Several environmental pollutants have been reported to exhibit either pro-angiogenic or anti-angiogenic effects, which may contribute to related vascular diseases. However, the specific mechanism by which pollutants induce sprouting angiogenesis is unclear, and there are few studies on the association between the site of hyperangiogenesis and vascular diseases. In this study, zebrafish were exposed to bisphenol S (BPS, 1~100 µg/L) and tetrabromobisphenol S (TBBPS, 0.1 and 10 µg/L) from the embryonic to the larval stage to investigate how pollutants interfere with the function of ectopic sprouting vessels. Results showed that BPS and TBBPS promoted ectopic sprouting angiogenesis in different types of vascular plexus at different developmental time points but inhibited vascular endothelial-cadherin (VE-cadherin) expression. The proteomic analyses on eGFP-positive endothelial cells isolated from Tg(flk1: eGFP) zebrafish indicated that both BPS and TBBPS induced ectopic angiogenesis through inhibiting VE-cadherin-mediated adherens junction and activating the downstream pro-angiogenic signaling. In ectopic sprouting vessels induced by BPS and TBBPS, an increased endothelial permeability resulted in white blood cells recruitment and erythrocyte retention. Human oxidized lipids were also prone to deposit in these ectopic vessels following BPS and TBBPS exposure. This suggests that ectopic angiogenesis is a cause of vascular dysfunction and related diseases.