S1P (Sphingosine-1-Phosphate)–Induced Vasodilation in Human Resistance Arterioles During Health and Disease

Abstract

Background: Preclinical studies suggest that S1P (sphingosine-1-phosphate) influences blood pressure regulation primarily through NO-induced vasodilation. Because microvascular tone significantly contributes to mean arterial pressure, the mechanism of S1P on human resistance arterioles was investigated. We hypothesized that S1P induces NO-mediated vasodilation in human arterioles from adults without coronary artery disease (non–coronary artery disease) through activation of 2 receptors, S1PR 1 (S1P receptor 1) and S1PR 3 (S1P receptor 3). Furthermore, we tested whether this mechanism is altered in vessels from patients diagnosed with coronary artery disease. methods: Human arterioles (50–200 µm in luminal diameter) were dissected from otherwise discarded surgical adipose tissue, cannulated, and pressurized. Following equilibration, resistance vessels were preconstricted with ET-1 (endothelin-1) and changes in internal diameter to increasing concentrations of S1P (10-12 to 10-7 M) in the presence or absence of various inhibitors were measured. Results: S1P resulted in significant dilation that was abolished in vessels treated with S1PR 1 and S1PR 3 inhibitors and in vessels with reduced expression of each receptor. Dilation to S1P was significantly reduced in the presence of the NOS (NO synthase) inhibitor Nω-nitro-L-arginine methyl ester and the NO scavenger 2-4-(carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide. Interestingly, dilation was also significantly impaired in the presence of PEG-catalase (polyethylene glycol–catalase), apocynin, and specific inhibitors of NOX (NADPH oxidases) 2 and 4. Dilation in vessels from patients diagnosed with coronary artery disease was dependent on H 2 O 2 alone which was only dependent on S1PR 3 activation. Conclusions: These translational studies highlight the inter-species variation observed in vascular signaling and provide insight into the mechanism by which S1P regulates microvascular resistance and ultimately blood pressure in humans.

Integrated metabolomics analysis reveals mechanistic insights into variability in blood pressure response to thiazide diuretics and beta blockers

“…The final outcome of S1P signaling can be either vasodilatation or vasoconstriction, mainly depending on the expression levels of the different S1PR subtypes. Moreover, it is hypothesized that S1PRs' expression and signaling are altered in patients with HTN 18 …”

“…S1P signaling induces different effects on the vasculature, depending on the S1P receptor subtypes: activation of the endothelial S1PR 1 and 3 leads to vasodilatation through production of the vasodilator NO, whereas stimulation of the smooth muscle S1PR 2 and 3 results in vasoconstriction via Rho kinase signaling. 17 , 18 The final outcome of S1P signaling can be either vasodilatation or vasoconstriction, mainly depending on the expression levels of the different S1PR subtypes. Moreover, it is hypothesized that S1PRs' expression and signaling are altered in patients with HTN.…”

“…Moreover, it is hypothesized that S1PRs' expression and signaling are altered in patients with HTN. 18 …”

“…Moreover, it is hypothesized that S1PRs' expression and signaling are altered in patients with HTN. 18 TDs reduce BP mainly by increasing sodium excretion through inhibiting Na+/Cl-cotransporter in the kidneys. 19 BBs reduce BP mainly by reducing heart rate and cardiac output via blocking the action of catecholamines on the β1adrenergic receptors.…”

Shedding Light on the Roles of Ceramide in Human Microvascular Function

“…These findings challenge the concept that depending on the disease state, microvascular endothelial cells either produce NO or H 2 O 2 in response to flow and suggest a more graded transition from NO- to H 2 O 2 -mediated FIDs. In addition, the study findings raise questions about the relationship between H 2 O 2 and NO production because H 2 O 2 can increase eNOS expression and NO production in endothelial cells, 13 and in human arterioles, NO production in response to increasing doses of S1P requires formation of H 2 O 2 14 Small increases in H 2 O 2 in response to C2 ceramide or S1P/S1PR1 activators may have enhanced NO production, while larger increases in H 2 O 2 after treatment with inhibitors of the ceramide/S1P/S1PR1/3 pathway may have uncoupled eNOS and eliminated NO signaling. However, a concern about the dual-dependency phenomenon and the balance of endothelial H 2 O 2 and NO production observed in the current study is the use of C2 ceramide by the investigators.…”