title: Differential Effects of Long Term FTY720 Treatment on Endothelial versus Smooth Muscle Cell Signaling to S1P in Rat Mesenteric Arteries.
abstract: The sphingosine-1-phosphate (S1P) analog FTY720 exerts pleiotropic effects on the cardiovascular system and causes down-regulation of S1P receptors. Myogenic constriction is an important mechanism regulating resistance vessel function and is known to be modulated by S1P. Here we investigated myogenic constriction and vascular function of mesenteric arteries of rats chronically treated with FTY720. Wistar rats received FTY720 1mg/kg/daily for six weeks. At termination, blood pressure was recorded and small mesenteric arteries collected for vascular studies in a perfusion set up. Myogenic constriction to increased intraluminal pressure was low, but a sub-threshold dose of S1P profoundly augmented myogenic constriction in arteries of both controls and animals chronically treated with FTY720. Interestingly, endothelial denudation blocked the response to S1P in arteries of FTY720-treated animals, but not in control rats. In acute experiments, presence of FTY720 significantly augmented the contractile response to S1P, an effect that was partially abolished after the inhibition of cyclooxygenase (COX-)-derived prostaglandins. FTY720 down regulated S1P1 but not S1P2 in renal resistance arteries and in cultured human endothelial cells. This study therefore demonstrates the endothelium is able to compensate for the complete loss of responsiveness of the smooth muscle layer to S1P after long term FTY720 treatment through a mechanism that most likely involves enhanced production of contractile prostaglandins by the endothelium.
authors: Department of Clinical Pharmacy and Pharmacology, Department of Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Mahdi
authors: M
authors: Hamidi Shishavan
authors: Department of Clinical Pharmacy and Pharmacology, Department of Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Arash
authors: A
authors: Bidadkosh
authors: Division of Nephrology, Department of Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Saleh
authors: S
authors: Yazdani
authors: Department of Clinical Pharmacy and Pharmacology, Department of Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Sebastiaan
authors: S
authors: Lambooy
authors: Division of Nephrology, Department of Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Jacob
authors: J
authors: van den Born
authors: Department of Clinical Pharmacy and Pharmacology, Department of Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Hendrik
authors: H
authors: Buikema
authors: Department of Clinical Pharmacy and Pharmacology, Department of Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Robert H
authors: RH
authors: Henning
authors: Department of Clinical Pharmacy and Pharmacology, Department of Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Leo E
authors: LE
authors: Deelman
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D008638:Mesenteric Arteries / Q000166:cytology* / Q000502:physiology; D024510:Muscle Development / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects*; D011312:Pressure; D051381:Rats; D017208:Rats, Wistar; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine