Flow-Regulated Endothelial S1P Receptor-1 Signaling Sustains Vascular Development

Abstract

SUMMARY During angiogenesis, nascent vascular sprouts fuse to form vascular networks enabling efficient circulation. Mechanisms that stabilize the vascular plexus are not well understood. Sphingosine 1-phosphate (S1P) is a blood-borne lipid mediator implicated in the regulation of vascular and immune systems. Here we describe a mechanism by which the G protein-coupled S1P receptor-1 (S1P1) stabilizes the primary vascular network. A gradient of S1P1 expression from the mature regions of the vascular network to the growing vascular front was observed. In the absence of endothelial S1P1, adherens junctions are destabilized, barrier function is breached, and flow is perturbed resulting in abnormal vascular hypersprouting. Interestingly, S1P1 responds to S1P as well as laminar shear stress to transduce flow-mediated signaling in endothelial cells both in vitro and in vivo. These data demonstrate that blood flow and circulating S1P activate endothelial S1P1 to stabilize blood vessels in development and homeostasis.

Sphingosine 1-phosphate receptor 1 regulates the directional migration of lymphatic endothelial cells in response to fluid shear stress

“…Consistent with this possibility, a previous study reported that S1PR1 inhibition or knockdown in HUVECs significantly decreased cell alignment in response to spatially uniform fluid flow [23]. Furthermore, the response of these cells to fluid flow could be reconstituted with R120A S1PR1, which cannot be activated by S1P, suggesting that S1PR1 might be activated by fluid shear stress independent of its ligand [23]. However, in our system, S1P appears to be required for the response of HLMVECs to WSS (figure 4).…”

“…Notably, measurements using a Förster resonance energy transfer-based sensor suggest that bradykinin B 2 undergoes changes in conformation and activity in response to fluid shear stress, consistent with a direct role in flow sensing [22]. Recent evidence likewise implicates sphingosine 1-phosphate receptor 1 (S1PR1), another GPCR, in the response of endothelial cells to fluid flow [23]. S1PR1 knockout & 2016 The Author(s) Published by the Royal Society.…”

“…How S1PR1 contributes to vessel stabilization is incompletely understood. However, previous work shows that the presence of S1PR1 was required for human umbilical vein ECs (HUVECs) to initiate downstream signalling via ERK1/2 specifically in response to WSS [23].…”

“…mice die in utero between E13.5 and E14.5 due to defects in vascular stabilization [23][24][25][26][27]. How S1PR1 contributes to vessel stabilization is incompletely understood.…”

The role of sphingosine-1-phosphate in the tumor microenvironment and its clinical implications

“…5,16 In endothelial cells, S1PR1 and S1PR2 are essential in vascular development. [42][43][44][45] Stimulation of S1PR1 and/or S1PR3 often promotes cell proliferation and migration in normal and cancer cells, while S1PR2 may inhibit the signaling that promotes cell proliferation and migration. 46-48 "Inside-out" signaling of S1P plays a pivotal role in cancer cells and in the TME by stimulating the S1P receptors, especially S1PR1-3, on each cell type.…”