Neonatal HDL Counteracts Placental Vascular Inflammation via S1P–S1PR1 Axis

Abstract

Placental inflammation and dysfunction during pregnancy are associated with short- and long-term adverse outcomes for the offspring. However, the mechanisms of vascular protection at the feto-placental interface are still poorly investigated. The high-density lipoprotein (HDL) associated sphingosine-1-phosphate (S1P) has been described as a powerful anti-inflammatory complex. This study aimed to elucidate the role of cord blood-derived HDL (nHDL) in feto-placental endothelial dysfunction. Here, we report that the exposure of primary fetal placental arterial endothelial cell (fPAEC) to healthy nHDL-S1P attenuated the ability of TNFα to activate NF-κB signaling and increase the expression of pro-inflammatory markers. Moreover, the angiotensin II (AngII)-induced reactive oxygen species (ROS) production was blunted in the presence of nHDL, whereas it was preserved when the cells were preincubated with S1P receptor antagonists, suggesting that S1P accounts for the vascular protective function of nHDL at the feto-placental unit. These results highlight the importance of HDL and S1P metabolism and signaling in pregnancy pathophysiology.

Fetal High-Density Lipoproteins: Current Knowledge on Particle Metabolism, Composition and Function in Health and Disease

“…Moreover, Del Gaudio and colleagues observed that fetal HDL induces vasorelaxation of precontracted placental chorionic arteries [ 134 ]. The same authors further investigated the role of cord blood-derived HDL and S1P on the fetoplacental endothelium [ 138 ]. Primary fetal placental endothelial cells were approached by and challenged with TNFα to induce inflammation.…”

“…Primary fetal placental endothelial cells were approached by and challenged with TNFα to induce inflammation. They showed that incubation with fetal HDL-S1P complex from healthy donors diminished the ability of TNFα to activate signaling of NF-κB and expression of pro-inflammatory markers [ 138 ]. Angiotensin II is a stimulator of NADPH oxidase, which produces reactive oxygen species, leading to a vascular inflammatory response [ 139 ].…”

“…Angiotensin II is a stimulator of NADPH oxidase, which produces reactive oxygen species, leading to a vascular inflammatory response [ 139 ]. After treatment of primary fetal placental endothelial cells with angiotensin II, the production of reactive oxygen species was blunted in the presence of fetal HDL-S1P, whereas it was preserved when pre-incubated with an S1P receptor antagonist, suggesting that S1P signaling accounts for some of the vasculoprotective functions of HDL at the fetoplacental endothelium [ 138 ].…”

“…Similar to the results in PE mothers [ 177 ], PON1 activity was also shown to be decreased in the cord blood of the newborns [ 182 ]. In another study, HDL isolated from cord blood of PE pregnancies was reported to be linked with significantly reduced levels of apoM [ 138 ]. Given that levels of S1P are usually highly correlated with apoM levels, these results suggest less endothelial protection by this bioactive lipid [ 138 ].…”

“…In another study, HDL isolated from cord blood of PE pregnancies was reported to be linked with significantly reduced levels of apoM [ 138 ]. Given that levels of S1P are usually highly correlated with apoM levels, these results suggest less endothelial protection by this bioactive lipid [ 138 ]. Additionally, HDL from PE mothers has been shown to be depleted in apoM as well as S1P, accompanied with less anti-oxidative capacity [ 183 ].…”