Pregnancy

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

Abstract
Sphingosine-1-phosphate (S1P) is a potent bioactive lipid and has been implicated in cardiovascular disease. The objective of this study was to determine vasoactive effects, and underlying mechanisms, of S1P on adult human maternal arteries. Isometric tension of omental and myometrial arteries, isolated from normal pregnant women at term, were assessed to incremental doses of S1P in the presence and absence of the nitric oxide synthase inhibitor, N (G)-nitro-L-arginine methyl ester (L-NAME). The putative involvement of Rho-associated kinases (ROCKs) in intact arteries, and those permeabilized with alpha-toxin to study agonist-dependent calcium-sensitization, was assessed with the inhibitor Y27632. QRT-PCR established the presence of mRNA encoding S1P receptors, endothelial differentiation gene receptors (EDG) 1, 3, 5/S1P₁ to ₃, in both artery types. S1P induced a dose-dependent increase in isometric tension of all arteries. Y27632 reduced constriction to S1P in intact arteries and reduced S1P-induced sensitization of contraction to sub-maximal activating Ca²⁺ in permeabilized arteries. L-NAME also modulated S1P vasoactive responses in a tissue-specific manner. Two sub-groups of omental arteries were found to exist, one of which utilized the nitric oxide (NO) pathway. In myometrial arteries, S1P evoked oscillatory constrictions, but pretreatment of L-NAME resulted in only tonic constrictions of unaltered peak magnitude. The prominent vasoactive actions of S1P in maternal arteries of pregnant women are modulated by inhibitors of ROCKs and NO bioavailability. The subtle tissue-specific functional differences in modulation of S1P actions by NO has important implications for our consideration of vascular tone regulation during pregnancy by this bioactive circulatory metabolite.

Key words: Pregnancy • Nitric oxide • Rho-associated Kinase • Sphingosine-1-Phosphate • Vasoconstriction

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