Abstract
The blood-brain barrier (BBB) is formed by the endothelial cells lining cerebral microvessels, but how blood-borne signaling molecules influence permeability is incompletely understood. We here examined how the apolipoprotein M (apoM)-bound sphingosine 1-phosphate (S1P) signaling pathway affects the BBB in different categories of cerebral microvessels using ApoM deficient mice (Apom-/-). We used two-photon microscopy to monitor BBB permeability of sodium fluorescein (376 Da), Alexa Fluor (643 Da), and fluorescent albumin (45 kDA). We show that BBB permeability to small molecules increases in Apom-/- mice. Vesicle-mediated transfer of albumin in arterioles increased 3 to 10-fold in Apom-/- mice, whereas transcytosis in capillaries and venules remained unchanged. The S1P receptor 1 agonist SEW2871 rapidly normalized paracellular BBB permeability in Apom-/- mice, and inhibited transcytosis in penetrating arterioles, but not in pial arterioles. Thus, apoM-bound S1P maintains low paracellular BBB permeability in all cerebral microvessels and low levels of vesicle-mediated transport in penetrating arterioles.
Highlights
The blood-brain barrier (BBB) allows only certain molecules and cells to pass from the blood circulation to the brain
To assess the BBB with all structural constituents we used two-photon fluorescence imaging in vivo in transgenic apolipoprotein M (apoM)-deficient mice (Apom-/-) mice (Christoffersen et al, 2011), which in contrast to other animal models, e.g. S1pr1iECKO (S1pr1 knock-out) mice (Yanagida et al, 2017), retain expression and function of S1PR1 (Christoffersen et al, 2011)
The increased fluorescence accumulation in the brains of Apom-/- mice and reduced accumulation of fluorophores in the brains of SEW2871treated Apom-/- mice were not caused by different kinetics of a fluorophore clearance from the blood stream or differences in blood pressure. These results show that apoM shortage increases the BBB permeability towards small molecules (~0.3–0.7 kDa), and that the effect can be reversed by S1PR1 stimulation
Summary
The blood-brain barrier (BBB) allows only certain molecules and cells to pass from the blood circulation to the brain. Molecules cross the BBB via the paracellular route by diffusion between endothelial cells (Tietz and Engelhardt, 2015), or by transcellular route, including vesicular transport across the endothelium (De Bock et al, 2016). The loss of BBB function leads to increased permeability, which is viewed mainly as the consequence of disrupted junctional complexes at endothelial cell contact sites (Davies, 2002; Engelhardt et al, 2014; Salameh et al, 2016). Recent evidence suggests equal importance of transcytosis, as a failure in the homeostatic regulation of endothelial trans-cellular transport may aggravate brain pathologies (Knowland et al, 2014; Habgood et al, 2007; Hashizume and Black, 2002; Krueger et al, 2013)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
