S1P Signaling and De Novo Biosynthesis in Blood Pressure Homeostasis

Cantalupo, Anna; Lorenzo, Annarita Di

doi:10.1124/jpet.116.233205

Cited by 43 publications

(51 citation statements)

References 123 publications

(173 reference statements)

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“…Shear stress exerted by flowing blood induces the production and release of S1P by the endothelium 30 , contributing to the physiological activation of S1PR1 signaling in the vasculature 6 . Pharmacological inhibition of S1PR1 in MA significantly reduced flow-mediated vasodilation 6, 11 , and lack of S1PR1 in EC in vitro and thoracic aorta in vivo reduced eNOS activation in response to shear stress 22 , implicating S1PR1 signaling in the flow-mediated vasodilation upstream of NO production.…”

Section: Discussionmentioning

confidence: 96%

“…Recently, we reported that endothelial derived S1P has a great impact on systemic BP regulation via S1PR1-S1P-eNOS autocrine signaling 6, 11, 22 . Shear stress exerted by flowing blood induces the production and release of S1P by the endothelium 30 , contributing to the physiological activation of S1PR1 signaling in the vasculature 6 .…”

Section: Discussionmentioning

confidence: 99%

“…In addition to ATP, shear stress also stimulates endothelial release of S1P 30 . S1PR1 was shown to be necessary for flow-mediated primary vascular network formation in the retina, alignment of endothelial cells in response to flow-mediated Akt and eNOS activation 22 , and vasodilation of resistance arteries in response to flow 6, 11 , suggesting its critical involvement in biomechanical signaling in the endothelium.…”

Section: Discussionmentioning

confidence: 99%

“…S1PR3 is expressed in vascular smooth muscle cells (VSMC) of various vascular beds 9, 10 , and along with S1PR2 induce vasoconstriction via Gq-coupled Ca 2+ /IP 3 and G13-coupled RhoA/Rho kinase pathway 11, 12 . On the contrary, endothelial S1PR3 mediates HDL-bound-S1P induced vasodilation of thoracic aorta ex-vivo via eNOS-derived NO production 13 .…”

Section: Introductionmentioning

confidence: 99%

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S1PR1 (Sphingosine-1-Phosphate Receptor 1) Signaling Regulates Blood Flow and Pressure

et al. 2017

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Nitric oxide is one of the major endothelial-derived vasoactive factors that regulate blood pressure and the bioactive lipid mediator S1P is a potent activator of endothelial nitric oxide synthase through G-protein coupled receptors. Endothelial-derived S1P and the autocrine/paracrine activation of S1P receptors play an important role in preserving vascular functions and blood pressure homeostasis. Furthermore, FTY720, binding to four out of five S1PRs recently approved by the FDA to treat autoimmune conditions, induces a modest and transient decrease in heart rate in both animals and humans, suggesting that drugs targeting sphingolipid signaling affect cardiovascular functions in vivo. However, the role of specific S1P receptors in BP homeostasis remains unknown. The aim of this study is to determine the role of the key vascular S1P receptors, namely, S1PR1 and S1PR3 in BP regulation in physiological and hypertensive conditions. The specific loss of endothelial S1PR1 decreases basal and stimulated endothelial-derived NO, and re-sets blood pressure to a higher-than-normal value. Interestingly, we identified a novel and important role for S1PR1 signaling in flow-mediated mechanotransduction. FTY720 (fingolimod), acting as functional antagonist of S1PR1, markedly decreases endothelial S1PR1, increases blood pressure in control mice and exacerbates hypertension in Ang-II mouse model, underlining the anti-hypertensive functions of S1PR1 signaling. Our study identifies S1P-S1PR1-NO signaling as a new regulatory pathway in vivo of vascular relaxation to flow and blood pressure homeostasis, providing a novel therapeutic target for the treatment of hypertension.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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S1PR1 (Sphingosine-1-Phosphate Receptor 1) Signaling Regulates Blood Flow and Pressure

et al. 2017

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“…S1P activation of endothelial S1P receptors induces eNOS-dependent NO secretion and vasodilation (48). We showed that ApoM-Fc–S1P potently reduced blood pressure in a sustained manner (~190 hours) in AngII-induced hypertensive mice.…”

Section: Discussionmentioning

confidence: 99%

An engineered S1P chaperone attenuates hypertension and ischemic injury

et al. 2017

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Endothelial dysfunction, a hallmark of vascular disease, is restored by plasma high-density lipoprotein (HDL). However, a generalized increase in HDL abundance is not beneficial, suggesting that specific HDL species mediate protective effects. Apolipoprotein M–containing HDL (ApoM+HDL), which carries the bioactive lipid sphingosine 1-phosphate (S1P), promotes endothelial function by activating G protein–coupled S1P receptors. Moreover, HDL-bound S1P is limiting in several inflammatory, metabolic, and vascular diseases. We report the development of a soluble carrier for S1P, ApoM-Fc, which activated S1P receptors in a sustained manner and promoted endothelial function. In contrast, ApoM-Fc did not modulate circulating lymphocyte numbers, suggesting that it specifically activated endothelial S1P receptors. ApoM-Fc administration reduced blood pressure in hypertensive mice, attenuated myocardial damage after ischemia/reperfusion injury, and reduced brain infarct volume in the middle cerebral artery occlusion model of stroke. Our proof-of-concept study suggests that selective and sustained targeting of endothelial S1P receptors by ApoM-Fc could be a viable therapeutic strategy in vascular diseases.

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Reticulon 3 regulates sphingosine‐1‐phosphate synthesis in endothelial cells to control blood pressure

Jin,

Chang,

Chen

et al. 2024

MedComm

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The discovery of the endothelium as a major regulator of vascular tone triggered intense research among basic and clinical investigators to unravel the physiologic and pathophysiologic significance of this phenomenon. Sphingosine‐l‐phosphate (S1P), derived from the vascular endothelium, is a significant regulator of blood pressure. However, the mechanisms underlying the regulation of S1P biosynthetic pathways in arteries remain to be further clarified. Here, we reported that Reticulon 3 (RTN3) regulated endothelial sphingolipid biosynthesis and blood pressure. We employed public datasets, patients, and mouse models to explore the pathophysiological roles of RTN3 in blood pressure control. The underlying mechanisms were studied in human umbilical vein endothelial cells (HUVECs). We reported that increased RTN3 was found in patients and that RTN3‐null mice presented hypotension. In HUVECs, RTN3 can regulate migration and tube formation via the S1P signaling pathway. Mechanistically, RTN3 can interact with CERS2 to promote the selective autophagy of CERS2 and further influence S1P signals to control blood pressure. We also identified an RTN3 variant (c.116C>T, p.T39M) in a family with hypertension. Our data provided the first evidence of the association between RTN3 level changes and blood pressure anomalies and preliminarily elucidated the importance of RTN3 in S1P metabolism and blood pressure regulation.

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S1P Signaling and De Novo Biosynthesis in Blood Pressure Homeostasis

Cited by 43 publications

References 123 publications

S1PR1 (Sphingosine-1-Phosphate Receptor 1) Signaling Regulates Blood Flow and Pressure

S1PR1 (Sphingosine-1-Phosphate Receptor 1) Signaling Regulates Blood Flow and Pressure

An engineered S1P chaperone attenuates hypertension and ischemic injury

Reticulon 3 regulates sphingosine‐1‐phosphate synthesis in endothelial cells to control blood pressure

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