Vascular dysfunction in S1P2 sphingosine 1-phosphate receptor knockout mice.
There is growing evidence that sphingosine 1-phosphate (S1P) plays an important role in regulating the development, morphology, and function of the cardiovascular system. There is little data, however, regarding the relative contribution of endogenous S1P and its cognate receptors (referred to as S1P(1-5)) to cardiovascular homeostasis. We used S1P(2) receptor knockout mice (S1P(2)(-/-)) to evaluate the role of S1P(2) in heart and vascular function. There were no significant differences in blood pressure between wild-type and S1P(2)(-/-) mice, measured in awake mice. Cardiac function, evaluated in situ by using a Millar catheter, was also not different in S1P(2)(-/-) mice under baseline or stimulated conditions. In vivo analysis of vascular function by flowmetry revealed decreases in mesenteric and renal resistance in S1P(2)(-/-) mice, especially during vasoconstriction with phenylephrine. In intact aortic rings, the concentration-force relations for both KCl and phenylephrine were right shifted in S1P(2)(-/-) mice, whereas the maximal isometric forces were not different. By contrast, in deendothelialized rings the concentration-force relations were not different but the maximal force was significantly greater in S1P(2)(-/-) aorta. Histologically, there were no apparent differences in vascular morphology. These data suggest that the S1P(2) receptor plays an important role in the function of the vasculature and is an important mediator of normal hemodynamics. This is mediated, at least in part, through an effect on the endothelium, but direct effects on vascular smooth muscle cannot be ruled out and require further investigation.
Lorenz
John N
JN
Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0576, USA. lorenzjn@uc.edu
Arend
Lois J
LJ
Robitz
Rachel
R
Paul
Richard J
RJ
MacLennan
A John
AJ
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002316:Cardiotonic Agents / Q000494:pharmacology; D004280:Dobutamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009129:Muscle Tonus / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D011189:Potassium Chloride / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000502:physiology*; D012039:Regional Blood Flow / Q000502:physiology; D012079:Renal Circulation / Q000187:drug effects; D013152:Splanchnic Circulation / Q000187:drug effects; D014652:Vascular Diseases / Q000503:physiopathology*; D014655:Vascular Resistance / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D002316:Cardiotonic Agents; D049349:Receptors, Lysosphingolipid; D014662:Vasoconstrictor Agents; D004280:Dobutamine; D011189:Potassium Chloride