Sphingosine-1-phosphate receptors and the development of the vascular system

Abstract

Extracellular sphingolipid signaling has been implicated as an essential event in vascular development. Sphingosine-1-phosphate (S1P), through interactions with G protein-coupled receptors, regulates functions of endothelial and smooth muscle cells (SMCs)—the major cell types of the vasculature. The knockout of the gene encoding the S1P₁ receptor (formally known as Edg-1) in mice blocks vascular maturation, the process where SMCs and pericytes envelop nascent endothelial tubes. The question that remains is how stimulation of S1P receptors controls this critical event in the developmental sequence leading to the formation of functional blood vessels.

Introduction

Sphingolipids are a structurally diverse class of molecules that function as organizers of membrane structure and as mediators of cellular signals [1], [2]. A number of sphingolipid metabolites including ceramide, sphingosine, sphingosylphosphorylcholine, and sphingosine-1-phosphate (S1P) are involved in cell signaling pathways regulating important processes including proliferation, apoptosis, inflammation, and cell mobility [3], [4], [5], [6]. Although functioning intracellularly in many cases, some sphingolipid signaling molecules are exported from cells to exert their effects extracellularly and serve as a conduit of communication between cells [5], [7]. The paradigm for an extracellular sphingolipid–mediated signaling pathway is S1P and its G protein-coupled receptors.

S1P is produced intracellularly with the degradation of ceramide by ceramidase to liberate sphingosine [8]. Sphingosine is phosphorylated by sphingosine kinase to yield S1P [9], [10], which can be recycled back to sphingosine by a specific S1P phosphatase [11], [12], [13] or degraded by an S1P lyase [14], [15], [16]. Although S1P appears to be produced in all cells, it is found in high amounts in platelets [17], which lack the S1P lyase and, as a consequence, the ability to degrade S1P [18], [19]. The release of S1P from activated platelets [20], [21], [22] and the active secretion of S1P from hematopoietic cells [23] leads to the high levels of S1P found in plasma and serum, estimated to be approximately 0.2 and 0.5 μM, respectively [17], [24].

When added to cells, S1P triggers several activities including proliferation, migration, cytoskeletal changes, adhesion molecule expression and anti-apoptotic effects [25], [26], [27], [28], [29]. Many of these activities are produced via the interaction of S1P with G protein-coupled receptors. The first receptor identified, Edg-1 (now renamed S1P₁), was found as an abundantly expressed gene in differentiating endothelial cells (ECs) [30]. Initially an orphan, S1P₁ was shown later to bind S1P with high affinity and specificity [31], [32] and to initiate a G_i-mediated signaling pathway [33], [34], [35], [36]. Ultimately, a family of five structurally related receptors have been identified for S1P. Although related in their sequence, these receptors are distinctive in their cell and tissue distribution, the G protein pathways that they trigger and the biological activities that they mediate [4], [37], [38]. Recently, S1P receptor signaling has emerged as an important event in the formation of new blood vessels [35], [39]. As a prelude to the discussion on the role of S1P receptors in this process, we will describe some of the other key signaling pathways in blood vessel formation.