European Heart Journal Advance Access originally published online on March 23, 2007
European Heart Journal 2007 28(7):777-779; doi:10.1093/eurheartj/ehm025
Sphingomyelin metabolism and endothelial cell function
Academic Medical Center, Department of Pharmacology and Pharmacotherapy, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
* Corresponding author. Tel: +31-20-566-6762; fax: +31-20-696-5976. E-mail address: m.c.michel{at}amc.uva.nl
This editorial refers to ‘Secretory sphingomyelinase is upregulated in chronic heart failure: a second messenger system of immune activation relates to body composition, muscular functional capacity, and peripheral blood flow’
by W. Doehner et al., on page 821
Serum activity of the enzyme secretory sphingomyelinase (sSM) is higher in patients with congestive heart failure (CHF) than in those with arterial hypertension or in healthy controls; more importantly, this elevation is not related to the aetiology of CHF, but rather to its severity, and well correlated with peak oxygen uptake, cytokine activation, skeletal muscle strength, and peripheral vasodilator capacity.1 In a proportional hazard analysis, serum sSM activity was related to survival independent of age, NYHA class, or blood pressure. As sSM is largely derived from the endothelium, these findings highlight the emerging role of endogenous sphingolipids as regulators of cardiovascular function and the role of the endothelium in such regulation. Against this background, we will highlight some recent findings on the complex interplay between the local formation of sphingomyelin metabolites and the endothelium.
Sphingomyelin metabolite-mediated signalling
Various stressful stimuli can activate different isoforms of sphingomyelinase, which catalyses the hydrolysis of sphingomyelin to ceramide. Ceramidase can metabolize ceramide further into sphingosine, which in turn can be phosphorylated by sphingosine kinase (SphK) to yield sphingosine-1-phosphate (S1P). Other enzymes allow for a reversal of such reactions and/or can form other biologically active sphingomyelin metabolites such as sphingosylphosphorylcholine. S1P is a ligand for at least five subtypes of G-protein coupled receptors, designated S1P1–5, which were originally described as endothelial differentiation genes. S1P1–3 are the major S1P receptor subtypes expressed in the cardiovascular system, in both endothelium and vascular smooth muscle cells; at least at the mRNA level, S1P1 appears to be the most abundantly expressed subtype in the endothelium.2 In many cases, ceramide and sphingosine on the one and S1P on the other hand have opposite effects on cellular function, e.g. by stimulating cell death and apoptosis vs. cell growth and differentiation, respectively. Accordingly, sphingomyelinases determine the amount of sphingomyelin metabolites being formed and hence can be considered as a volume regulator of sphingolipid signalling. On the other hand, SphK has a major effect on the balance between the opposing effects of ceramide/sphingosine and those of S1P and hence may allow determining the direction of such signalling.
Sphingomyelin metabolites can reach endothelial cells via the blood stream. Perhaps even more importantly, they can be formed locally in the vascular wall,3–10 as endothelial cells express the enzymes involved in sphingolipid metabolism and are a regulatable source of sphingomyelin metabolites. As the endothelium also expresses receptors for some sphingomyelin metabolites such as the S1P receptor subtypes S1P1 and S1P3,2 they can be considered as autocrine and/or paracrine mediators of endothelial function.
Classically, endothelial cells were considered to mainly provide a barrier between the bloodstream and the vascular smooth muscle cells. This barrier function is based upon tight junctions between the endothelial cells. Endocytosis at the apical and subsequent exocytosis at the basolateral surface of the endothelium allows a controlled transition from the lumen to the vessel wall. Several agents can affect this endothelial barrier function via direct effects on the integrity of the tight junctions. It has now been recognized that the sphingomyelin metabolites ceramide and S1P have profound (opposite) effects on endothelial barrier function.2 Local sphingolipid metabolism, induced for instance by activation of sphingomyelinase or SphK, may therefore regulate endothelial permeability, most likely via differential actions on endothelial cell–cell junctions. Indeed, Göggel et al.6 have shown in vivo and in a perfused lung model that platelet activating factor (PAF)-induced pulmonary oedema is partly mediated by local ceramide generation. In this study, it was shown that PAF increased sSM activity and thereby elevated lung ceramide content. This effect was completely abolished in acidic sphingomyelinase-deficient mice, and in these animals, PAF-induced lung oedema was strongly reduced when compared with wild-type animals. Therefore, it can be concluded that the local production of ceramide by the action of sphingomyelinase can increase vascular permeability, leading to tissue oedema. In light of the study by Doehner et al., it is tempting to speculate that the increased sphingomyelinase activity observed in CHF patients possibly contributes to heart-failure-associated pulmonary oedema.
The endothelium forms and releases mediators controlling vascular smooth muscle tone, among which formation of the relaxant factor nitric oxide (NO) by endothelial NO synthase (eNOS) may be the most important. Local formation of ceramide by neutral sphingomyelinase can cause endothelium-dependent vasorelaxation through endothelial NO production.8 This activation of eNOS has been shown not to involve cytosolic Ca2+ elevation, but is probably mediated by translocation of eNOS from the plasma membrane caveolae to the perinuclear region. It cannot be excluded that metabolites of ceramide cause these effects, as also locally formed S1P has been shown to activate eNOS to stimulate the endothelial NO formation.5 For example, angiotensin II can induce an SphK-dependent activation of eNOS in the endothelium, which counteracts the contractile response to angiotensin II; interestingly, both the endothelial S1P formation and the direct contraction of the smooth muscle appear to occur via the same receptor subtype, i.e. the AT1 receptor.9 Therefore, a disturbed sphingolipid metabolism in the vascular wall could lead to a reduced NO bioavailability and endothelial dysfunction and contribute to the development of vascular pathologies. As CHF is a state of endothelial dysfunction, such mechanisms might contribute to the association between serum sSM activity and peripheral vasodilator capacity.1
Doehner et al.1 also reported an association between serum sSM activity and cytokine activation, specifically with circulating levels tumour necrosis factor-
(TNF-) and soluble TNF- receptor 1. Several pro-inflammatory stimuli including cytokines such as interleukin-1ß, lipopolysaccharides, and oxidative stress can increase serum activity of sSM. Thus, the endogenous formation of sphingomyelin metabolites in endothelial cells is part of the downstream signalling of TNF-.5 Upon stimulation of human endothelial cells with TNF-, the activation of eNOS was preceded by the sequential activation of neutral sphingomyelinase-2 and SphK-1 and, therefore, the generation of S1P. Sphingolipid metabolism-dependent production of NO was linked to inhibition of expression of E-selectin and the adhesion of dendritic cells to the endothelium stimulation by TNF-. However, high concentrations of S1P may directly induce expression of VCAM-1 and E-selectin; thus the role of S1P in adhesion is complex and not yet fully understood.
Weibel–Palade bodies are granules stored in the endothelium, which contain various pro-coagulant and pro-inflammatory substances. One of the effects of both locally formed S1P7 and ceramide4 is triggering exocytocis of Weibel–Palade bodies by the endothelium. These bodies release vasoactive substances in close proximity of the endothelial cell, resulting in the initiation of vascular thrombosis and inflammation. However, S1P can also activate eNOS, which forms NO and in turn inhibits exocytosis of Weibel–Palade bodies. Although these data appear contradictory for S1P, the two-faced effect of S1P allows for a tight regulation of the release of Weibel–Palade bodies by sphingomyelin metabolites upon pro-inflammatory stimulation. As the formation of atherosclerotic lesions occurs through activation of cellular events that include monocyte adhesion to the endothelium and vascular inflammation, local formation of S1P may play an important role in the pathogenesis of atherosclerotic vascular disease.
Vascular maturation during embryonic blood vessel development involves cell-to-cell communication and interactions between endothelial and vascular smooth muscle cells to form a solid new vascular structure. In conditional mutant mice with a specific deletion of S1P1 from endothelial cells endothelial tubes are formed, but they are incompletely covered by smooth muscle cells. This leads to embryonic haemorrhage and interuterine death.3 This indicates that the endothelial S1P1 receptor is required for vascular maturation. The origin of the S1P acting on the S1P1 receptor in the endothelial tube has not been investigated, but due to the absence of blood flow through those vessel precursors, it could be hypothesized that the required S1P is produced locally by the endothelial cell itself.
The role of sphingomyelin metabolites during blood vessel development is not limited to vascular maturation, as S1P can also upregulate expression of the proteolytic enzymes matrix metalloproteinases (MMPs).10 MMPs are involved in degradation of the extracellular matrix and play critical roles in endothelial cell migration and matrix remodelling during angiogenesis and collateral growth. Therefore, S1P formed by sequential activation of sphingomyelinase, ceramidase, and SphK may also play an important role in endothelial cell invasion during blood vessel formation by regulating the expression of MMPs.
Taken together, endothelial cells express various enzymes involved in the sphingolipid metabolism and can therefore endogenously form sphingomyelin metabolites. As the endothelium is responsive to sphingomyelin metabolites, particularly due to expression of S1P receptors, sphingomyelin metabolites appear to be auto- and paracrine regulators of endothelial function. This may play a role during embryogenesis and also in pathological conditions involving endothelial dysfunction, such as vascular inflammation and/or CHF.
Conflict of interest: none declared.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society Cardiology.
doi:10.1093/eurheartj/ehl541 
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[Abstract/Free Full Text]
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