Testosterone regulates the expression and functional activity of
sphingosine-1-phosphate receptors in the rat corpus
, Yu-ming Guo
, Ping Chen
, He Xiao
, Xing-huan Wang
, Michael E DiSanto
Department of Rehabilitation, Zhongnan Hospital of Wuhan University, Wuhan, China
Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China
Surgery and Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, USA
Received: December 25, 2016; Accepted: September 12, 2017
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 con-
traction 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 con-
trols, surgical castration and T supplemented group. Serum S1P levels were detected by high-performance liquid chromatography. The expres-
sion 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 expres-
sion 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 cas-
tration 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 dys-
regulation may contribute to hypogonadism-related erectile dysfunction (ED), and S1P receptors may be expected as a potential target for treat-
Penile erection is a neurovascular event involving the relaxation of
corpus cavernosum smooth muscle (CCSM), which is maintained
tonically contracted state in majority of the time [1–3]. Although
many studies have investigated CCSM relaxation pathways, few have
focused on the role of the contractile apparatus in erectile function
(EF). Similarly, the major therapeutic treatments available for ED have
primarily targeted CCSM relaxation pathways with particular empha-
sis on NO/cyclic guanosine monophosphate (cGMP) signalling [3–5].
Shingosine-1-phosphate (S1P), a member of a large family of lipid
metabolites termed sphingolipids, represents one of the key latest addi-
tions to the list of ‘vasoactive’ substances that modulate vascular tone
. S1P is produced by sphingosine kinases (SphK) catalyzing the
ATP-dependent phosphorylation of sphingosine. Thus far, two different
SphK isoforms have been found in mammals named SphK1 and SphK2
. SphK1 is predominantly cytosolic and pro-survival, while SphK2
functions mainly in the endoplasmic reticulum and stimulates apoptosis
but its role is still poorly understood [6–8]. In plasma, S1P can reach a
concentration of 0.1–4 lM . Besides vasoactive potential, S1P is
capable of regulating a wide array of biological processes such as cell
proliferation, migration, survival, differentiation and others [6, 8, 10].
Many of these cellular responses are initiated by S1P binding to and
These authors contributed equally to this work.
*Correspondence to: Dr. Xin-hua ZHANG MD, Ph.D.
ª 2017 The Authors.
Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
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J. Cell. Mol. Med. Vol 22, No 3, 2018 pp. 1507-1516