S1PR1 (Sphingosine-1-Phosphate Receptor 1) Signaling Regulates Blood Flow and Pressure. Academic Article uri icon

Overview

abstract

  • Nitric oxide is one of the major endothelial-derived vasoactive factors that regulate blood pressure (BP), and the bioactive lipid mediator S1P (sphingosine-1-phosphate) is a potent activator of endothelial nitric oxide synthase through G protein-coupled receptors. Endothelial-derived S1P and the autocrine/paracrine activation of S1PR (S1P receptors) play an important role in preserving vascular functions and BP homeostasis. Furthermore, FTY720 (fingolimod), binding to 4 out of 5 S1PRs recently approved by the Food and Drug Administration 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 nitric oxide and resets BP to a higher-than-normal value. Interestingly, we identified a novel and important role for S1PR1 signaling in flow-mediated mechanotransduction. FTY720, acting as functional antagonist of S1PR1, markedly decreases endothelial S1PR1, increases BP in control mice, and exacerbates hypertension in angiotensin II mouse model, underlining the antihypertensive functions of S1PR1 signaling. Our study identifies S1P-S1PR1-nitric oxide signaling as a new regulatory pathway in vivo of vascular relaxation to flow and BP homeostasis, providing a novel therapeutic target for the treatment of hypertension.

publication date

  • June 12, 2017

Research

keywords

  • Blood Pressure
  • Fingolimod Hydrochloride
  • Hypertension
  • Nitric Oxide
  • Nitric Oxide Synthase Type III
  • Receptors, Lysosphingolipid

Identity

PubMed Central ID

  • PMC5531041

Scopus Document Identifier

  • 85020745990

Digital Object Identifier (DOI)

  • 10.1161/HYPERTENSIONAHA.117.09088

PubMed ID

  • 28607130

Additional Document Info

volume

  • 70

issue

  • 2