Serotonin activates angiogenic phosphorylation signaling in human endothelial cells

► Serotonin activates angiogenic-signaling kinases in human endothelial cells. ► HTR1B expressed in human endothelial cells is involved in angiogenic signaling. ► Serotonin and VEGF stimulate a same set of signaling kinases in tumor environment. Serotonin, a known neurotransmitter, also functions as an angiokine to promote angiogenesis. The majority of serotonin in the human body is stored in platelets, and platelet aggregation leads to significant release of serotonin in thrombotic tumor environment. We have investigated serotonin signaling in human endothelial cells. Through G-protein-coupled receptors, serotonin at physiologically relevant concentrations activated Src/PI3K/AKT/mTOR/p70S6K phosphorylation signaling, and this activation was similar to that seen with VEGF. This finding provides insight into the overlapping angiogenic signaling pathways stimulated by serotonin in tumor environment, and suggests one of the mechanisms underlying resistance to current VEGF-targeting antiangiogenic therapy against cancer.