Arsenic requires sphingosine‐1‐phosphate type 1 receptors to induce angiogenic genes and endothelial cell remodeling

Arsenic increases risk and incidence of cardiovascular diseases and cancers. Arsenic affects multiple vascular beds to promote liver sinusoidal capillarization and portal hypertension, ischemic heart disease, peripheral vascular disease, and tumor angiogenesis. The mechanism for initiating arsenic signaling in endothelial calls is unknown. We found that arsenic‐stimulated cell signaling and angiogenic gene expression in human microvascular endothelial cells (HMVEC) were Pertussis toxin sensitive indicating a G‐protein coupled signaling pathway. Both the sphingosine‐1‐phosphate type 1 receptor (S1P1) inhibitor VPC23019 and siRNA knockdown of S1P1 blocked arsenic‐stimulated HMVEC angiogenic gene expression and tube formation, but not induction of HMOX1or IL8. S1P1 was enriched on liver sinusoidal endothelial cells (LSEC) in vivo and VPC23019 inhibited arsenic‐stimulated oxidant generation and capillarization. These studies identified novel roles for S1P1 in mediating arsenic stimulation of both angiogenesis and pathogenic LSEC capillarization, as well as demonstrated a novel role for S1P1 in mediating environmental responses in the liver vasculature. Thus, they provide possible mechanistic insight into arsenic‐promoted vascular pathogenesis and disease promotion.

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