sphingosine-1-phosphate and Hemorrhage

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 the placenta. Taken together, these results suggest that ACER2 sustains the integrity of the placental vasculature by controlling the homeostasis of sphingolipids in mice.

Topics: Alkaline Ceramidase; Animals; Female; Hemorrhage; Lysophospholipids; Mice; Mice, Inbred C57BL; Mice, Knockout; Placenta; Pregnancy; Sphingolipids; Sphingosine; Vascular Diseases

Topics: Animals; Brain; Brain Ischemia; Fingolimod Hydrochloride; Hemoglobins; Hemorrhage; Lymphocytes; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myeloid Cells; Reperfusion Injury; RNA, Messenger; Sphingosine; Sphingosine 1 Phosphate Receptor Modulators; Sphingosine-1-Phosphate Receptors; Stroke; T-Lymphocytes; Thrombocytopenia; Up-Regulation

Intimate communication between neural and vascular cells is critical for normal brain development and function. Germinal matrix (GM), a key primordium for the brain reward circuitry, is unique among brain regions for its distinct pace of angiogenesis and selective vulnerability to hemorrhage during development. A major neonatal condition, GM hemorrhage can lead to cerebral palsy, hydrocephalus, and mental retardation. Here we identify a brain-region-specific neural progenitor-based signaling pathway dedicated to regulating GM vessel development. This pathway consists of cell-surface sphingosine-1-phosphate receptors, an intracellular cascade including Gα co-factor Ric8a and p38 MAPK, and target gene integrin β8, which in turn regulates vascular TGF-β signaling. These findings provide insights into region-specific specialization of neurovascular communication, with special implications for deciphering potent early-life endocrine, as well as potential gut microbiota impacts on brain reward circuitry. They also identify tissue-specific molecular targets for GM hemorrhage intervention.

Topics: Brain; Embryo, Mammalian; Enzyme Activation; Fingolimod Hydrochloride; Guanine Nucleotide Exchange Factors; Hemorrhage; Humans; Integrin beta Chains; Lysophospholipids; Mutation; Neostriatum; Neovascularization, Physiologic; Neural Pathways; Neural Stem Cells; Organ Specificity; p38 Mitogen-Activated Protein Kinases; Phenotype; Receptors, Lysosphingolipid; Reward; Signal Transduction; Sphingosine; Transforming Growth Factor beta