Short Periods of Hypoxia Upregulate Sphingosine Kinase 1 and Increase Vasodilation of Arteries to Sphingosine 1-Phosphate (S1P) via S1P₃

Abstract

Sphingosine kinase [(SK), isoforms SK1 and SK2] catalyzes the formation of the bioactive lipid, sphingosine 1-phosphate (S1P). This can be exported from cells and bind to S1P receptors to modulate vascular function. We investigated the effect of shortterm hypoxia on SK1 expression and the response of arteries to S1P. SK1 expression in rat aortic and coronary artery endothelial cells was studied using immunofluorescence and confocal microscopy. Responses of rat aortic rings were studied using wire myography and reversible hypoxia induced by bubbling myography chambers with 95% N 2 :5% CO 2 . Inhibitors were added 30 minutes before induction of hypoxia. S1P induced endothelium-dependent vasodilation via activation of S1P 3 receptors and generation of nitric oxide. Hypoxia significantly increased relaxation to S1P and this was attenuated by (2R)-1- [[(4-[[3-methyl-5-[(phenylsulfonyl)methyl] phenoxy]methyl]phenyl]methyl]-2-pyrrolidinemethanol [(PF-543), SK1 inhibitor] but not (R)-FTY720 methyl ether [(ROMe), SK2 inhibitor]. Hypoxia also increased vessel contractility to the thromboxane mimetic, 9,11-dideoxy-11a,9a-epoxymethanoprostaglandin F2a, which was further increased by PF-543 and ROMe. Hypoxia upregulated SK1 expression in aortic and coronary artery endothelial cells and this was blocked by PF-543 and 2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole [(SKi), SK1/2 inhibitor]. The effects of PF-543 and SKi were associated with increased proteasomal/lysosomal degradation of SK1. A short period of hypoxia increases the expression of SK1, which may generate S1P to oppose vessel contraction. Under hypoxic conditions, upregulation of SK1 is likely to lead to increased export of S1P from the cell and vasodilation via activation of endothelial S1P 3 receptors. These data have significance for perfusion of tissue during episodes of ischemia.H.A. and T.A.M.A. were supported by a scholarship from the Libyan Government. O.J.K. was sponsored by a scholarship from the Iraqi Government.

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“…A molecular study of arterial responses under short-term hypoxic conditions demonstrated arterial dilatation mediated by various receptors. [28] In the present study, although patients were examined during the acute phase of disease, the observed changes in PD may have been caused by short-term hypoxia. Similarly, studies that investigated the relationship between retinal veins and oxygen saturation reported a wider diameter of retinal veins under lower arterial oxygen saturation levels.…”

Integrin α5 Is Regulated by miR-218-5p in Endothelial Progenitor Cells

“…Endothelial cells are known to be exquisitely sensitive to oxygen depletion even after short intervals of time. [46][47][48][49] Integrin cell adhesion molecules displayed on the cell surface regulate the interaction between endothelial cells, the extracellular matrix, and circulating intraluminal cell populations. 17,50 Here we showed ITGA5 protein localized to the surface of kEPCs was modulated first by the binding of mature miR-218-5p to ITGA5 mRNA transcript within the coding sequence.…”

“…The investigations reported here outline the specific function of one mature miRNA, miR-218-5p, in mammalian kEPCs responding to a hypoxic environment (Figure 8). Endothelial cells are known to be exquisitely sensitive to oxygen depletion even after short intervals of time 46 – 49 . Integrin cell adhesion molecules displayed on the cell surface regulate the interaction between endothelial cells, the extracellular matrix, and circulating intraluminal cell populations 17 , 50 .…”

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