Maternal and fetal alkaline ceramidase 2 is required for placental vascular integrity in mice

Abstract

Sphingolipids have been implicated in mammalian placental development and function, but their regulation in the placenta remains unclear. Herein we report that alkaline ceramidase 2 (ACER2) plays a key role in sustaining the integrity of the placental vasculature by regulating the homeostasis of sphingolipids in mice. The mouse alkaline ceramidase 2 gene (Acer2) is highly expressed in the placenta between embryonic day (E) 9.5 and E12.5. Acer2 deficiency in both the mother and fetus decreases the placental levels of sphingolipids, including sphingoid bases (sphingosine and dihydrosphingosine) and sphingoid base-1-phosphates (sphingosine-1-phosphate and dihydrosphingosine-1-phosphate) and results in the in utero death of ≈50% of embryos at E12.5 whereas Acer2 deficiency in either the mother or fetus has no such effects. Acer2 deficiency causes hemorrhages from the maternal vasculature in the junctional and/or labyrinthine zones in E12.5 placentas. Moreover, hemorrhagic but not non-hemorrhagic Acer2-deficient placentas exhibit an expansion of parietal trophoblast giant cells with a concomitant decrease in the area of the fetal blood vessel network in the labyrinthine zone, suggesting that Acer2 deficiency results in embryonic lethality due to the atrophy of the fetal blood vessel network in | 15253 LI et aL.

Adipocyte-Derived Exosomal NOX4-Mediated Oxidative Damage Induces Premature Placental Senescence in Obese Pregnancy

“…In the thresholded images, the total placental section area was marked using the “free-hand selections” tool, and the area fraction, ie, the percentage of the specifically stained area to the total tissue section area, was obtained using the “measure” tool under the “Analyze” panel in Fiji. 25 …”

Leaky Gut Plays a Critical Role in the Pathophysiology of Autism in Mice by Activating the Lipopolysaccharide-Mediated Toll-Like Receptor 4–Myeloid Differentiation Factor 88–Nuclear Factor Kappa B Signaling Pathway

“…Fiji software, an open-source image-processing package based on ImageJ (Media Cybernetics, Inc., Rockville, MD, USA), was used to measure the fractional area and integrated optical density (IOD) of the stained slides as reported in our previous study [ 22 ]. To summarize, first, the microscopic image of each tissue stained with IHC was transformed into an 8-bit grayscale.…”

Mysterious sphingolipids: metabolic interrelationships at the center of pathophysiology

“…Loss of ACER2 in either the mother or the fetus resulted in placental vascular defects, leading to fetal growth restriction, placental thrombosis, and fetal demise. ACER2 plays a critical role in maintaining sphingolipid homeostasis in the placenta, which is necessary for proper vascular function ( Li et al, 2020 ). Moreover, ACER2 is upregulated in response to DNA damage and the loss of ACER2 or its bioactive product sphingosine impairs the DNA damage response and increases genomic instability ( Xu et al, 2016 ).…”