Modulation of Human Arterial Tone During Pregnancy: The Effect of the Bioactive Metabolite Sphingosine-1-Phosphate1

Abstract

Sphingosine-1-phosphate (S1P) is a potent bioactive lipid that has been implicated in cardiovascular disease. The objective of the present study was to determine the vasoactive effects and underlying mechanisms of S1P on adult human maternal arteries. The isometric tensions of the omental and myometrial arteries isolated from normal pregnant women at term were assessed in response to incremental doses of S1P in the presence or absence of the nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). The putative involvement of Rho-associated kinases (ROCKs) in intact arteries and in those permeabilized with alpha-toxin, to study agonist-dependent calcium-sensitization, was assessed with the inhibitor Y27632. Real-time RT-PCR established the presence of mRNA encoding the S1P receptors (S1P(1) to (3)), previously known as endothelial differentiation gene receptors (EDG1, 3 and 5), in both artery types. S1P induced a dose-dependent increase in the isometric tension of all the arteries. Y27632 reduced constriction due to S1P in intact arteries and reduced S1P-induced sensitization of contraction to submaximal activating Ca(2+) in permeabilized arteries. L-NAME also modulated S1P vasoactive responses in a tissue-specific manner. Two subgroups of omental arteries were identified, one of which utilizes the NO pathway. In myometrial arteries, S1P evoked oscillatory constrictions, whereas pretreatment with L-NAME resulted in only tonic constrictions of unaltered peak magnitude. The prominent vasoactive actions of S1P in the maternal arteries of pregnant women are modulated by inhibitors of ROCKs and NO bioavailability. The subtle tissue-specific functional differences in the modulation of S1P actions by NO have important implications for vascular tone regulation by this bioactive circulatory metabolite during pregnancy.

Maternal disturbance in activated sphingolipid metabolism causes pregnancy loss in mice

“…Recently, it has been reported that S1P inhibits cytotrophoblast differentiation and could be involved in the pathogenesis of preeclampsia in humans (47). Furthermore, S1P has been shown to induce a dose-dependent vasoconstriction in human uterine arteries during pregnancy (48). Given these results and the results in our study, disturbance in sphingolipid metabolism may be relevant to human reproductive failure.…”

Human uterine and placental arteries exhibit tissue-specific acute responses to 17 -estradiol and estrogen-receptor-specific agonists

“…The present study is important for identifying (i) that estrogen differentially regulates human uterine and placental vascular tone; (ii) the potential of ER-specific agonists to act as tissue-specific modulators of human uteroplacental vascular tone; (iii) adding to an evolving narrative in the literature whereby circulatory, or locally produced, factors may differentially alter the tone of human myometrial or placental arteries (Hemmings et al , 2006; Hudson et al , 2007; Corcoran et al , 2012). It is of interest that subcutaneous arteries isolated from post-menopausal healthy women relaxed more to PPT than 17β-estradiol and the effects of either agent were unaltered by NOS inhibition (Cruz et al , 2008)—results that were different to that which we observed in maternal myometrial arteries.…”

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.…”