Sphingosine-1-Phosphate Acts via Rho-Associated Kinase and Nitric Oxide to Regulate Human Placental Vascular Tone1

Abstract

Sphingosine-1-phosphate (S1P), a bioactive lipid released from activated platelets, has been demonstrated in animal models to regulate vascular tone through receptor-mediated activation of Rho-associated kinase 1 and nitric oxide synthase 3. The role of S1P in regulation of human vascular tone (particularly during pregnancy, with its unique vascular adaptations and localized platelet activation) is unknown. We hypothesized that S1P would constrict small placental arteries through activation of Rho-associated kinases with modulation by nitric oxide. Reverse transcription-polymerase chain reaction of chorionic plate artery preparations detected mRNAs encoding all five receptors for S1P, and S1P induced dose-dependent vasoconstriction of both chorionic plate and stem villous isobarically mounted arteries, which at 10 micromol/L was 32.9% +/- 3.86% (mean +/- SEM) and 34.6% +/- 7.01%, respectively. In stem villous arteries, S1P-induced vasoconstriction was enhanced significantly following inhibition of nitric oxide synthases with N(G)-nitro-L-arginine methyl ester (100 micromol/L, 52.6% +/- 6.28%, P < 0.05). The S1P-induced vasoconstriction was reversed by Y27632, an inhibitor of Rho-associated kinases (10 micromol/L) in both chorionic plate (to 14.9% +/- 4.95%) and stem villous arteries (to 2.71% +/- 6.13%). The S1P added to alpha-toxin-permeabilized, isometrically mounted chorionic plate arteries bathed in submaximal Ca(2+)-activating solution induced Ca(2+)-sensitization of constriction, which was 47.7% +/- 10.0% of that occurring to maximal Ca(2+)-activating solution. This was reduced by Y27632 to 18.4% +/- 18.4%. Interestingly, S1P-induced vasoconstriction occurred in all isobarically mounted arteries but was inconsistent in isometrically mounted chorionic plate arteries. In summary, S1P-induced vasoconstriction in human placental arteries is mediated by increased Ca(2+)-sensitization through activation of Rho-associated kinases, and this vasoconstriction also is modulated by nitric oxide. Identification of these actions of S1P in the placental vasculature is important for understanding both normal and potentially abnormal vascular adaptations with pregnancy.

Progesterone-induced sphingosine kinase-1 expression in the rat uterus during pregnancy and signaling consequences

“…Lysophospholipids have been shown to be involved in reproductive processes, such as implantation (55), angiogenesis during decidualization (40), and regulation of placental vascular tone (15). There is evidence to suggest a role for LPA in the induction of labor in that autotaxin activity in serum increases during the third trimester of pregnancy, reaching higher levels in patients with threatened preterm delivery (49).…”

S1P Signaling and De Novo Biosynthesis in Blood Pressure Homeostasis

“…Moreover, S1P signaling regulates the myogenic response to pressure. (Coussin et al, 2002;Salomone et al, 2003;Scherer et al, 2006), as well as in human resistance arteries, including omental and myometrial arteries from pregnant women (Hudson et al, 2007), placenta and stem villous arteries (Hemmings et al, 2006), and porcine retinal arterioles (Kamiya et al, 2014). Mouse S1P 10 nM-30 mM + eNOS (L-NAME) Roviezzo et al (2006) Akt, protein kinase B; BAPTA, 1,2-bis(o-aminophenoxy)ethane-N,N,N9N9-tetraacetic acid; FTY720-P, FTY20 phosphate; L-NAME, L-N G -nitroarginine methyl ester; N.R., not reported; PTX, pertussis toxin; SD, Sprague Dawley; 2, absence of endothelium; +, presence of endothelium.…”

Sphingosine-1-phosphate and modulation of vascular tone

“…In support of this hypothesis, pharmacological as well as genetic experiments have shown that S1P 2 and/or S1P 3 receptor subtypes coupled with ROK may mediate S1P-provoked vasoconstriction in VSMCs. 60,70,77,78 It has also been shown that pharmacological inhibition of NOS activity leads to an enhancement of S1P-elicited vasoconstriction, 76,79 and conversely, S1P fails to induce vasorelaxation in eNOS null animals. 29 Further support for differential receptor-mediated vasorelaxation and vasoconstriction responses comes from studies in which S1P 1 antagonists were found to potentiate S1P-induced vasoconstriction responses in rodent cerebral arteries; however, effects of S1P 1 receptor antagonism are lost when the endothelium is removed from the blood vessel preparation.…”