Blood-borne sphingosine 1-phosphate maintains vascular resistance, blood pressure, and cardiac function in mice
Abstract
Sphingosine 1-phosphate (S1P) is a bioactive lipid that circulates in plasma bound to high-density lipoproteins (HDL) and albumin. Circulating S1P levels correlate positively with systolic blood pressure (BP) in hypertension and negatively with severity in septic shock and with left ventricular function in heart disease. In mice, isolated deficiency in HDL-S1P and endothelial cell S1P receptor (R)-1 both trigger hypertension, supporting an essential role for HDL-S1P in endothelial function. Physiological roles of albumin-S1P and myocyte S1PRs in the cardiovascular system remain incompletely defined. We report that mice lacking all circulating S1P pools display hypotension and lack of BP increase with age, which contrasts with HDL-S1P deficiency and suggests an essential role for albumin-S1P in cardiovascular homeostasis. Although cardiac output was preserved in a basal state, left ventricular systolic function and contractile reserve were reduced in the absence of circulating S1P. Cardiac function and BP were partially or fully normalized by transfusion of erythrocytes capable of S1P production. Hypotension was accompanied by reduced peripheral resistance, and albumin-S1P, but not S1P complexed to an HDL-like chaperone, dose-dependently increased vascular resistance in isolated perfused kidneys via S1PR3 and S1PR2. Epistatic analysis supported a critical role for S1PR3 in S1P-dependent BP maintenance and pointed to a distinct origin of the cardiac phenotype. We thus uncover an essential role for circulating S1P in maintaining BP and left ventricular systolic function in mice. Our results also highlight distinct functions for the pools of S1P bound to HDL and to albumin, carrying both diagnostic and therapeutic implications.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (25)
Ilaria Del Gaudio
Université Paris Cité, Paris Cardiovascular Research Centre, INSERM U970
Philippe Bonnin
Physiologie Clinique - Explorations-Fonctionnelles, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris
Emilie Vessiéres
MitoVasc Department, Team 2 (CarMe), Angers University Hospital, CNRS, INSERM U1083, Angers University
Estelle Robidel
Université Paris Cité, Paris Cardiovascular Research Centre, INSERM U970
Manuela C. Garcia
MitoVasc Department, Team 2 (CarMe), Angers University Hospital, CNRS, INSERM U1083, Angers University
Coralyne Proux
MitoVasc Department, Team 2 (CarMe), Angers University Hospital, CNRS, INSERM U1083, Angers University
Alexandre Boutigny
Physiologie Clinique - Explorations-Fonctionnelles, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris
Véronique Baudrie
Université Paris Cité, Paris Cardiovascular Research Centre, INSERM U970
Hoa T. T. Ha
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore
Ludovic Couty
Université Paris Cité, Paris Cardiovascular Research Centre, INSERM U970
Sandrine Placier
INSERM UMR-S 1155, Sorbonne Université
Ivo Cornelissen
Cardiovascular Research Institute, Department of Medicine, University of California
Nicolo Faedda
Université Paris Cité, Paris Cardiovascular Research Centre, INSERM U970
Nesrine Mebrek
Université Paris Cité, Paris Cardiovascular Research Centre, INSERM U970
Théo Morel
Université Paris Cité, Paris Cardiovascular Research Centre, INSERM U970
Anja Nitzsche
Université Paris Cité, Paris Cardiovascular Research Centre, INSERM U970
Tovo David
Cardiovascular Research Institute, Department of Medicine, University of California
Stéphanie Baron
Université Paris Cité, Paris Cardiovascular Research Centre, INSERM U970
Olivia Lenoir
Pierre-Louis Tharaux
Maria-Christina Zennaro
Université Paris Cité, Paris Cardiovascular Research Centre, INSERM U970
Long N. Nguyen
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore
Timothy Hla
Daniel Henrion
MitoVasc Department, Team 2 (CarMe), Angers University Hospital, CNRS, INSERM U1083, Angers University
Eric Camerer
Université Paris Cité, Paris Cardiovascular Research Centre, INSERM U970