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American Journal of Physiology - Renal Physiology logoLink to American Journal of Physiology - Renal Physiology
. 2019 Aug 7;317(3):F638–F640. doi: 10.1152/ajprenal.00572.2018

Sphingosine-1-phosphate signaling in blood pressure regulation

Suttira Intapad 1,
PMCID: PMC6766635  PMID: 31390266

Abstract

Sphingolipids were originally believed to play a role only as a backbone of mammalian cell membranes. However, sphingolipid metabolites, especially sphingosine-1-phosphate (S1P), are now recognized as new bioactive signaling molecules that are critically involved in numerous cellular functions of multiple systems including the immune system, central nervous system, and cardiovascular system. S1P research has accelerated in the last decade as new therapeutic drugs have emerged that target the S1P signaling axis to treat diseases of the immune and central nervous systems. There is limited knowledge of the specific effects on cardiovascular disease. This review discusses the current state of knowledge regarding the role of S1P on the regulation of blood pressure, vascular tone, and renal functions.

Keywords: blood pressure, renal function, sphingosine-1-phosphate, vascular tone

INTRODUCTION

Sphingosine-1-phosphate (S1P) is a multifunctional bioactive lipid mediator involved in various physiological processes. S1P is generated via phosphorylation of sphingosine by two sphingosine kinases (SphKs), SphK1 and SphK2, and can be eliminated by dephosphorylation reactions catalyzed by S1P-specific phosphatases and degraded by S1P lyase (SPL) (2, 27, 29). The major sources of S1P production are erythrocytes (16), endothelial cells (35, 36), and platelets (26, 37). S1P exerts its effect by binding to a family of five G protein-coupled receptors: S1P receptor (S1PR)1–SIPR5 (6, 22). Only S1PR1, S1PR2, and S1PR3 are widely expressed in the cardiovascular system, including the vasculature, heart, and kidney. S1PR4 is predominantly expressed in the lung and lymphoid system, whereas S1PR5 is found mainly in the brain (6, 22). Differential signaling of S1P is determined by the type of S1P receptor and its localization. Each S1PR couples with ≥1 heterodimeric G protein and specific downstream effectors. This coupling largely determines the nature of the cellular responses elicited by S1PRs (5, 9, 25). An important role of S1P signaling has been implicated in developmental angio- and morphogenesis of the heart, kidney, brain, and auditory system (32). Triple deletion of S1PR1–S1PR3 in mice results in failure to form cardiovascular system embryonic development and embryonic death (23). The role of S1P in regulating lymphocyte trafficking and inflammatory reduction has brought it into the clinical arena as a pharmacological target for autoimmune diseases (for a more extensive review, see Ref. 24).

Recently, FTY720 (Fingolimod), a nonspecific S1PR agonist, was approved by the Food and Drug Administration to treat autoimmune conditions. Interestingly, intravenous administration of FTY720 induced a transient decrease in heart rate (HR) and blood pressure (BP) in anesthetized rats (14) and humans during phase 3 clinical trials (7), suggesting a previously unrecognized role of this drug in cardiovascular function. Although there is evidence suggesting that S1P signaling may be involved in the modification of BP (3, 4, 7, 8, 18), more investigations are needed to clarify its role in BP regulation both in the physiological state and during hypertension. This review will summarize the most recent advances concerning the role of S1P in the regulation of BP homeostasis.

S1P AND BP HOMEOSTASIS

Analysis of the gene interaction network in human populations suggests that the sphingolipid metabolic network is considerably involved in the regulation of BP and hypertension (12, 13). When FTY720 was approved for the treatment of multiple sclerosis and then showed a previously unrecognized cardiovascular effect, research rapidly focused on the exact role of S1P signaling in BP regulation. Although many currently available pharmacological S1PR agonists and antagonists serve as important tools to decipher the role of S1PRs in different biological systems (5), very few studies using in vivo models have investigated the specific role of S1PR1, S1PR2, or S1PR3 signaling in BP regulation. One early study showed that S1P induced a rapid and transient decrease in HR and mean arterial pressure in rats (33). Forrest et al. (14) additionally demonstrated a transient decrease in HR and mean arterial pressure in anesthetized rats in response to intravenous administration of S1P, whereas continuous infusion of S1P was predominantly associated with an increase in BP in both conscious rats and mice. Recently, Cantalupo et al. (8) showed the potential antihypertensive role of the specific S1PR1 signaling pathway. The S1PR1 agonist SEW2871 induced a marked decrease in systolic BP in angiotensin II-induced hypertensive mice (∼25-mmHg decrease), but one that did not affect HR. Notably, the hypotensive effects of S1P signaling are more pronounced in animals with acute or chronic hypertension (8) than in normotensive animals. Moreover, S1P and its synthetic/metabolic pathways have been shown to be imbalanced in patients with essential and pulmonary arterial hypertension (28).

S1P AND VASCULAR TONE

Regulation of vascular function by S1P signaling has been recognized (21, 22, 32, 34). S1PRs are present in the vasculature with different expression patterns in different cells. S1PR1 and S1PR3 are the predominant S1PRs expressed in endothelial cells, S1PR2 and S1PR3 are present in vascular smooth muscle cells, and S1PR4 and S1PR5 are not detectable in the vascular system (32, 34). S1P induces different effects on the vasculature, depending on the relative levels of dominant receptor subtypes in endothelial cells or smooth muscle cells and the accessibility of S1P to the receptors. S1P signaling through the endothelial receptors S1PR1 and S1PR3 generates the potent vasodilator nitric oxide via the phosphatidylinositol 3-kinase pathway, which counteracts with vasoconstrictive effects mediated through smooth muscle S1PR2 and S1PR3 via Rho kinase (18, 31). These effects are species and vessel specific. For example, S1P induces endothelial nitric oxide synthase-dependent vasorelaxation in epinephrine-preconstricted mesenteric arterioles derived from either rats or mice. S1P-induced vasoconstriction has been observed in canine basilar arteries, rodent cerebral arteries, and mesenteric resistance arteries from aged rats (for extensive reviews, see Refs. 17 and 30). A recent study has demonstrated that a change in flow can increase the production of local S1P in endothelial cells that further activates S1PR1-induced vasodilation, suggesting the mechanotransduction autocrine loop of S1P-S1PR1 in controlling vascular tone (8, 20). However, the difference between local and circulating S1P production on the regulation of vascular tone during physiological and pathological conditions is unknown. Whether an imbalance of S1PR1–S1PR3 expression and its downstream cascade in endothelial cells and smooth muscle cells might lead to increased vascular tone and high BP in a pathological state needs further investigation.

S1P AND KIDNEY FUNCTION

Normal kidney function is central to the long-term control of BP. Although it is known that S1PR1, S1PR2, and S1PR3 and SphKs are present in the kidneys (1, 11, 22), there is limited information regarding the involvement of S1P in controlling kidney function in the normal physiological state. Most studies have focused on the important role of protecting the kidneys from ischemia from its anti-inflammatory properties (19). In the kidney, S1PR1–S1PR3 are found throughout the renal cortex, outer medulla, and inner medulla (38). S1P has been reported to mediate natriuresis via activation of S1PR1 in the renal medulla of rats, as acute infusion of S1P intravenously into the renal artery transiently reduces renal blood flow (3, 4, 10). Similarly, FTY720 infusion into the renal medulla also produces a substantial increase in urinary Na+ excretion and medullary blood flow (3, 4, 10). S1PR1 is believed to be a candidate gene that determines the response to salt in stroke-prone spontaneously hypertensive rats (15). Microarray gene expression and Western blot data from whole homogenized kidneys of salt-loaded stroke-prone spontaneously hypertensive rats show the lower expression of S1PR1, also known as endothelial differentiation gene 1, compared with Wistar-Kyoto rats (15). Given the essential role of the kidneys in the control of BP via regulating Na+ balance, it is possible that the renal S1P pathway is an important participant in the regulation of BP in the physiological state and may potentially be involved in the mechanism of hypertension. The detailed role of the S1P-mediated natriuretic effect in the regulation of BP requires further investigation.

CONCLUSIONS

This review has summarized recent evidence regarding S1P signaling in the regulation of BP homeostasis. Manipulation of S1P signaling may offer novel therapeutic approaches to the pathogenesis of hypertension. The action of S1P on BP regulation via regulation of vascular tone and kidney Na+ handling was also summarized. The action of S1P signaling is complex because it targets a variety of organ systems. Its effect on other systems or organs, for example, cardiac function, the immune system, and inflammation, needs to be considered in cardiovascular and BP regulation, especially during pathological conditions. Despite the rapid expansion of knowledge on S1P and enormous interest in using S1P-based drugs as therapy for cardiovascular disease, there is still little information available concerning its specific role in the pathophysiology of the cardiovascular system during hypertension. These knowledge gaps need further investigation.

GRANTS

This work was supported by the Norman Siegel Research Scholar Grant of the American Society of Nephrology Foundation for Kidney Research, American Heart Association Grant 16SDG27770041, National Institute of General Medical Sciences Grant P20-GM-109036, and startup funding from Tulane University.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author.

AUTHOR CONTRIBUTIONS

S.I. drafted manuscript; S.I. edited and revised manuscript; S.I. approved final version of manuscript.

ACKNOWLEDGMENTS

I acknowledge Nancy Busija for critical reading and editing of the manuscript.

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