Sphingosine‐1‐Phosphate Receptor 1 Mediated Vasodilation in Human Arterioles

Abstract

Precise regulation of vascular resistance is critical to maintain proper tissue perfusion. Recent data in animal models have shown that sphingolipids, a ubiquitous class of bioactive lipid messengers, can influence vasomotor tone via dilation or constriction. It has been suggested that sphingosine‐1‐phosphate (S1P) elicits vasodilation through generation of endothelial cell nitric oxide (NO) via activation of sphingosine‐1‐phosphate receptor 1 (S1PR1). We therefore examined the hypothesis that S1P is a regulator of human microvascular tone and elicits dilation via S1PR1‐induced increase in NO. Arterioles from healthy human adipose tissue were dissected and prepared for videomicroscopy, equilibrated and pre‐constricted with endothelin 1. Changes in arteriolar luminal diameter were recorded in response to increasing concentrations of S1P (10−12 to 10−6M) in the presence or absence of the S1PR1 receptor antagonist W146 (10−5M), nitric oxide synthase (NOS) inhibitor Nω‐nitro‐ l‐arginine (L‐NAME, 10−4M) or hydrogen peroxide (H2O2) scavenger polyethylene glycol‐catalase (peg‐Cat, 500U/ml). Administration of exogenous S1P induced vasodilation in healthy vessels to a maximal dilation of 63.7%±5.0, n=8 (mean±SEM). As with previous animal studies, vascular constriction was observed with higher, but still physiological levels of S1P (10−6 M). Vasodilation due to S1P was reduced following inhibition of S1PR1 compared to S1P alone (1.8%±4, n=5). In the presence of L‐NAME, S1P‐induced dilation decreased (9%±7.9, n=6). Interestingly, addition of peg‐Cat, an H2O2 scavenger, also decreased S1P‐induced dilation (11.1%±6.6, n=3). Together these data suggest that S1PR1 is a critical mechanistic component of S1P‐induced vasodilation in the human vasculature. Further, the S1P vasodilatory pathway may require formation of H2O2 in addition to NO.Support or Funding InformationThis research was supported by National Institute of Health (NHLBI) K08 HL141562‐02 (JKF)