Testosterone regulates the expression and functional activity of sphingosine‐1‐phosphate receptors in the rat corpus cavernosum

Abstract

The bioactive lipid sphingosine‐1‐phosphate (S1P) regulates smooth muscle (SM) contractility predominantly via three G protein‐coupled receptors. The S1P1 receptor is associated with nitric oxide (NO)‐mediated SM relaxation, while S1P2 & S1P3 receptors are linked to SM contraction via activation of the Rho‐kinase pathway. This study is to determine testosterone (T) modulating the expression and functional activity of S1P receptors in corpus cavernosum (CC). Adult male Sprague‐Dawley rats were randomly divided into three groups: sham‐operated controls, surgical castration and T supplemented group. Serum S1P levels were detected by high‐performance liquid chromatography. The expression of S1P1‐3 receptors and sphingosine kinases was detected by real‐time RT‐PCR. In vitro organ bath contractility and in vivo intracavernous pressure (ICP) measurement were also performed. T deprivation significantly decreased ICP rise. Meanwhile, surgical castration induced a significant increase in serum S1P level and the expression of S1P2‐3 receptors by twofold (P < 0.05) but a decrease in the expression of S1P1 receptor. Castration also augmented exogenous phenylephrine (PE), S1P, S1P1,3 receptor agonist FTY720‐P contractility and S1P2‐specific antagonist JTE013 relaxation effect. T supplemented could restore the aforementioned changes. We provide novel data that castration increased serum S1P concentration and up‐regulated the expression of S1P2‐3 receptors in CC. Consistently, agonizing S1P receptors induced CCSM contraction and antagonizing mediated relaxation were augmented. This provides the first clear evidence that S1P system dysregulation may contribute to hypogonadism‐related erectile dysfunction (ED), and S1P receptors may be expected as a potential target for treating ED.

S1P induces proliferation of pulmonary artery smooth muscle cells by promoting YAP-induced Notch3 expression and activation

“…Studies have demonstrated that S1PR2 and S1PR3 are the major types of S1PRs to transduce cellular effects of S1P in most of mammalian cell types ( 19 , 31 , 32 , 33 ). To examine whether S1PR2 and S1PR3 mediate S1P-induced activation of the STAT3/miR-135b/β-TrCP/YAP/Notch3 signal pathway and PASMCs proliferation, cells were previously treated with JTE013 (a selective S1PR2 antagonist, 10-μM) or CAY10444 (a selective S1PR3 antagonist, 10-μM) for 1 h and then stimulated with S1P, the phosphorylation level and total protein level of STAT3 and protein levels of β-TrCP, YAP, Notch3, and NICD3 were examined using Western blotting, the level of miRNA-135b was detected using qRT-PCR, and proliferation of cells was evaluated by the EdU incorporation assay.…”

“…S1P regulates cellular activities via five types of S1PRs in mammalian cells, and S1PR2 and S1PR3 are the major types to transduce cellular effects of S1P in most of cell types ( 19 , 31 , 32 , 33 ). Chen et al.…”

“…S1P regulates cellular activities via S1P receptors (S1PRs). Five types of S1PRs have been identified in mammalian cells, and S1PR2 and S1PR3 are the major types of S1PRs to transduce cellular effects of S1P in most of cell types ( 19 , 31 , 32 , 33 ). To address above hypothesis and to clarify which S1PR is involved in this process, we intervened STAT3, miR-135b, β-TrCP, YAP, Notch3, and S1PR2/3 in primary cultured PASMCs stimulated with exogenous S1P, separately.…”

Testosterone preserves endothelial function through regulation of S1P1/Akt/FOXO3a signalling pathway in the rat corpus cavernosum

“…Previous study demonstrated vascular endothelial cells expressed specific S1P1 receptors, which were important for regulating vascular tone in blood vessels, and that activation of S1P1 receptor promoted vascular relaxation via the eNOS pathway (Michel, Mulders, Jongsma, Alewijnse, & Peters, ). Moreover, Yin et al () reported testosterone activated S1P1 in the CC of castrated rats. S1P1 receptor was reported to activate the Akt pathway (Rosen, Gonzalez‐Cabrera, Sanna, & Brown, ), which was found to promote neuronal survival and anti‐apoptotic effects in many cell types (Hasegawa, Suzuki, Sozen, Rolland, & Zhang, ; Hemmati et al, ).…”

“…Safarian, Khallaghi, Ahmadiani, and Dargahi () reported activation of Sphingosine‐1‐phosphate (S1P) receptor‐regulated protein kinase B (Akt)/Forkhead box (FOXO) 3a pathway to enhance cell survival in response to oxidative stress. Moreover, Yin et al () suggested testosterone could enhance the activity of S1P receptor 1 (S1P1) in castrated rats. Similarly, S1P receptor‐mediated activation of Akt pathway protected granulosa cells against oxidative stress (Nakahara et al, ).…”