Sphingosine-1-phosphate receptor 1 controls endothelial cells permeability and function through the Bone morphogenetic 9/Endoglin signaling pathway

Signaling through Sphingosine-1-phosphate receptor 1 (S1PR1) contributes to maintain vascular integrity and stability. Bone morphogenetic 9 (BMP9) signaling through its associated co-receptor Endoglin was also identified as a vascular quiescence pathway but its relationship with the S1PR1 pathway is unclear. In this study, in vivo treatment in adult mice with S1PR1 inhibitors triggered the leakage of the pulmonary and tracheal vasculature. To explore the effect of S1PR1 and BMP9/Endoglin signaling axes on vascular growth in vivo, the blood vessels of retinas from newborn pups either treated with S1PR1 pharmacological inhibitors or infected with recombinant lentivirus allowing the expression of soluble Endoglin were stained with isolectin B4 fluorescent dye. The profound vascular defects upon disruption of either S1PR1 or BMP9 signaling support the positive roles of both pathways in neovasculogenesis. Moreover, S1P treatment of endothelial cells resulted in accumulation of Endoglin at the cell plasma membrane as demosntrated with immunofluorescence staining. The data suggest that S1P signaling is associated with activation of the phosphoinositide 3-kinase (PI3K) and extracellular–signal-regulated kinases (ERK) signaling pathway as well as enhanced BMP9-mediated SMAD phosphorylation. We propose that S1PR1 signals through the activation of the BMP9-Endoglin-SMAD pathway. Our results illustrate for the first time a regulatory effect of S1PR1 on the BMP9/Endoglin axis. We propose that this interaction plays a crucial role for the vessels function.