Background and purpose: Sphingosine 1-phosphate (S1P) selectively and potently constricts isolated cerebral arteries, but this response has not been pharmacologically characterized. Experimental approach: The receptor subtype(s) involved in S1P-induced cerebrovascular constriction were characterized using genetic (S1P 2 and S1P 3 receptor null mice) and pharmacological tools (phospho-FTY720, a S1P 1/3/4/5 receptor agonist; SEW2871, a S1P 1 receptor agonist, JTE-013, a S1P 2 receptor antagonist, VPC23019, a S1P 1/3 receptor antagonist). Isolated basilar or peripheral (femoral, mesenteric resistance) arteries, from either rat or mouse, were studied in a wire myograph. Key results: S1P concentration-dependently constricted basilar artery in rat, wild-type (WT) and S1P 2 null mice, but barely affected vascular tone in S1P 3 null mice. Vasoconstriction to U46619 (a thromboxane analogue) or to endothelin-1 did not differ between WT, S1P 2 and S1P 3 null mice. JTE-013 inhibited not only S1P-induced vasoconstriction, but also KCl-, U46619-and endothelin-1-induced constriction. This effect was observed in WT as well as in S1P 2 null mice. VPC23019 increased the concentration-dependent vasoconstriction to S1P in both rat and mouse basilar arteries with intact endothelium, but not in rat basilar artery without endothelium. Phospho-FTY720 concentration-dependently constricted rat basilar arteries, but not femoral or mesenteric resistance arteries, while SEW2871 did not induce any response in the same arteries. Conclusions and implications: S1P constricts cerebral arteries through S1P 3 receptors. The purported S1P 2 receptor antagonist JTE-013 does not appear to be selective, at least in rodents. Enhancement of S1P-induced contraction by VPC23019 might be related to blockade of S1P 1 receptors and NO generation.

Sphingosine-1-phosphate (S1P) is a lipid mediator that exerts multiple cellular functions through activation of a subfamily of G-protein-coupled receptors. Although there is evidence that S1P plays a role in the developing and adult CNS, little is known about the ability of brain parenchyma to synthesize this lipid. We have therefore analyzed the brain distribution of the enzymatic activity of the S1P synthesizing enzyme, sphingosine kinase (SPHK) [EC:2.7.1.91], as well as mRNA distribution for one of the two isoforms of this enzyme, sphingosine kinase 2. SPHK activity, measured by the conversion of [ 3 H]sphingosine to [ 3 H]S1P, is highest in cerebellum, followed by cortex and brainstem. Lowest activities were found in striatum and hippocampus. Sensitivity to 0.1% Triton-X suggests that this activity is accounted for by SPHK2. RT-PCR and in situ hybridization studies show that mRNA for this isoform has a distribution similar to that of SPHK activity. In vivo and in vitro ischemia increase SPHK activity and SPHK2 mRNA levels. These results indicate that SPHK2 is the predominant S1P-synthesizing isoform in normal brain parenchyma. Sphingosine-1-phosphate (S1P) exerts a wide variety of biological activities in many vertebrate cell types. It was initially proposed to act as a second messenger, based on the ability of extracellular growth factors to activate sphingosine kinase (SPHK) [EC:2.7.1.91] and increase intracellular S1P levels. However, the putative site that mediates these intracellular actions of S1P has not been identified. The discovery and cloning of five S1P receptors (S1P 1 /EDG 1 , S1P 2 /EDG 5 , S1P 3 /EDG 3 , S1P 4 /EDG 6 , and S1P 5 /EDG 8 ) has stimulated the notion that S1P acts as an extracellular signaling molecule, regulating a host of cellular functions such as proliferation, immunomodulation, apoptosis, migration, cytoskeletal organization, and differentiation/morphogenesis (Hla 2003 The present address of Kamil Topalkara is the Department of Neurology, Faculty of Medicine, Cumhuriyet University, Sivas, 58140 Turkey. 3 The present address of Margherita Popolo is the Service de Neurologie, Hôpital Pasteur, BP69, Av de la voie Romaine, 06002 Nice Cedex 1, France.Abbreviations used: BSA, bovine serum albumin; MCA, middle cerebral artery; OGD, oxygen glucose deprivation; PBS, phosphatebuffered saline; S1P, sphingosine-1-phosphate; SDS, sodium dodecyl sulphate; SPHK, sphingosine kinase.Journal of Neurochemistry, 2007Neurochemistry, , 103, 509-517 doi:10.1111Neurochemistry, /j.1471Neurochemistry, -4159.2007 Kleuser et al. 1998;Shu et al. 2002). Activated platelets represent a major source of S1P (English et al. 2000(English et al. , 2001Yatomi et al. 2000). S1P levels in serum are considerably higher than in plasma (0.4 vs. 0.1 lmol/L, respectively). However, the interaction of S1P with low-density lipoprotein (Kimura et al. 2001) might reduce the free concentration of S1P, possibly as a protection mechanism from full activation of vascular S1P receptors.The fact that the brain is ...

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ObjectivesTo review the evidence on how pregnancy, birth experience, breast feeding, parental responsiveness and sensitivity, and bonding and attunement were impacted by COVID-19.MethodsWe searched eight literature databases and websites of relevant UK-based organisations. The review focused on evidence during pregnancy and the early years (0–5 years). Studies of any study design published in English from 1 March 2020 to 15 March 2021 and conducted in high-income countries were included. Screening and data extraction were undertaken in duplicate. Evidence was synthesised using a narrative approach. Study quality of included studies was assessed using the Mixed Methods Appraisal Tool.ResultsThe search yielded 9776 publications, of which 26 met our inclusion criteria. Significant knowledge gaps on how COVID-19 affected pregnancy and breast feeding limited healthcare providers’ ability to provide consistent evidence-based information and care at the start of the pandemic. There was an enduring sense of loss about loved ones being restricted from taking part in key moments. Parents were concerned about the limitations of virtual healthcare provision. Some parents reported more opportunities for responsive breast feeding and improved parent–infant bonding due to reduced social and work pressures. Women from minoritised ethnic groups were less likely to continue breast feeding and attributed this to a lack of face-to-face support.ConclusionsThe evidence suggests that new and expectant families have been both negatively and positively impacted by the COVID-19 pandemic and the resulting restrictions. The impacts on parents’ opportunities to bond with their young children and to be attuned to their needs were felt unequally. It is important that emergency response policies consider the mother and the partner as a family unit when making changes to the delivery of maternal and child health and care services, so as to mitigate the impact on the family and existing health inequalities.PROSPERO registration numberCRD42021236769.