Blood-borne sphingosine 1-phosphate maintains vascular resistance, blood pressure, and cardiac function in mice

• 成果类型: Article
• 署名作者: Del Gaudio, Ilaria; Bonnin, Philippe; Vessieres, Emilie; Robidel, Estelle; Garcia, Manuela C.; Proux, Coralyne; Boutigny, Alexandre; Baudrie, Veronique; Ha, Hoa T. T.; Couty, Ludovic; Placier, Sandrine; Cornelissen, Ivo; Faedda, Nicolo; Mebrek, Nesrine; Morel, Theo; Nitzsche, Anja; David, Tovo; Baron, Stephanie; Lenoir, Olivia; Tharaux, Pierre-Louis; Zennaro, Maria-Christina; Nguyen, Long N.; Hla, Timothy; Henrion, Daniel; Camerer, Eric
• 署名单位: Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Universite Paris Cite; Assistance Publique Hopitaux Paris (APHP); Hopital Universitaire Lariboisiere-Fernand-Widal - APHP; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite d'Angers; Centre National de la Recherche Scientifique (CNRS); Centre Hospitalier Universitaire d'Angers; National University of Singapore; Institut National de la Sante et de la Recherche Medicale (Inserm); Sorbonne Universite; University of California System; University of California San Francisco; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard Medical School
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2512853123
• 发表日期: 2026-01-13
• 页码: 2512853123
• 关键词: sphingosine 1-phosphate; high-density lipoproteins; vascular resistance; blood pressure; heart failure; smooth-muscle; lymphocyte egress; heart-failure; SPHINGOSINE-1-PHOSPHATE; plasma; platelet; disease; S1P; hypertension; pathogenesis

摘要

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.