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.

Fingolimod inhibits proliferation and epithelial–mesenchymal transition in sacral chordoma by inactivating IL-6/STAT3 signalling

“…FTY720 is an immunosuppressive agent and is widely used in the treatment of autoimmune diseases, such as multiple sclerosis, asthma and several kinds of cancers, such as renal cancer, liver cancer and hepatic cancer [26][27][28]. Although many studies have demonstrated its excellent antitumour effects, to our knowledge, there have been no reports about its effect in sacrum chordoma [29,30]. Fortunately, our study concluded that FTY720 is as effective in sacrum chordoma as it is in other tumours.…”

Biocompatible Chemotherapy for Leukemia by Acid-Cleavable, PEGylated FTY720

“…Despite its high specificity and efficacy, clinical use of FTY720 for cancer therapy is restricted due to its capability of inducing profound bradycardia at an antineoplastic dose. − FTY720 is rapidly phosphorylated and becomes an agonist for G protein-coupled sphingosine 1 phosphate receptors (S1PRs), activating a signaling cascade in atrial myocytes that reduces heart rate. ,− Furthermore, phosphorylated FTY720 is also known to induce immunosuppression by inhibiting lymphocyte egress from the thymus and secondary lymphoid organs, resulting in lymphopenia, a reduction of peripheral lymphocytes . FTY720 analogues designed to prevent phosphorylation through conformational restraint were shown to eliminate these adverse effects. ,, The analogues down-regulate nutrient transport proteins and demonstrate potent anticancer efficacy in leukemia and prostate cancer models while maintaining normal heart rate.…”