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 selectivity of the BBB towards small molecules is maintained by tight and adherens junctions between adjoining endothelial cells (Tietz and Engelhardt, 2015), whereas the transport of large molecules is restricted by receptor-mediated interactions (De Bock et al., 2016). Under normal conditions, the BBB maintains low permeability due to the structural barrier maintained by junctional complexes and the low rate of transcytosis (De Bock et al., 2016; Daneman and Prat, 2015; Nico and Ribatti, 2012; Abbott et al., 2010). In disease states, 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). However, 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).

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid synthesized by all mammalian cells, with blood-circulating S1P produced by vascular endothelial cells, platelets, and erythrocytes (Thuy et al., 2014; Blaho and Hla, 2014; Xiong and Hla, 2014; Prager et al., 2015). S1P is a ligand for five membrane-bound G-protein-coupled receptors (S1PR1-5), and the brain endothelium expresses S1PR1-3 (Prager et al., 2015). The majority (~70%) of S1P in the blood circulation is transported by apolipoprotein M (apoM), a 26 kDa protein mainly associated with high-density lipoprotein (HDL) (Xu and Dahlbäck, 1999), while the remaining S1P fraction is carried primarily by albumin (Ruiz et al., 2017; Christoffersen et al., 2011).

Depending on the carrier (i.e., apoM or albumin), S1P preferentially activates S1PR1 or S1PR2 and S1PR3, which can exert opposite effects (Murata et al., 2000). For example, S1PR1 stimulation inhibits neuroinflammation, whereas S1PR2 and S1PR3 stimulation facilitates pro-inflammatory signaling cascades (Sanchez et al., 2007; Sanchez, 2016; Blaho et al., 2015). The onset and severity of sepsis in humans correlate with reduced apoM-S1P plasma concentrations and loss of BBB integrity (Davies, 2002; Kumaraswamy et al., 2012). In mice, lack of apoM compromises the endothelial barrier in the lungs and brown adipose tissue (Christoffersen et al., 2011; Christensen et al., 2016; Christoffersen et al., 2018), but its effects on the BBB are largely unexplored. First, apoM-deficient mice are less protected against neuroinflammation (Blaho et al., 2015). Second, conditional knock-out of S1PR1 increases the BBB permeability towards small molecules (Yanagida et al., 2017), but no data are available on how the BBB properties change with consistent S1PR1 expression, but during reduced apoM levels.

Our objective was to determine the modulatory role of apoM for the BBB. We used two-photon microscopy to image the brains of apoM-deficient (Apom^-/-) mice in vivo in order to characterize changes in BBB permeability in different categories of cerebral microvessels. Lack of apoM increased the BBB permeability to small molecules without affecting the ultrastructural components of junctional complexes and caused substantial increases in adsorptive transcytosis in pial and penetrating arterioles, but not in venules and capillaries. Systemic administration of a selective S1PR1 agonist SEW2871 promptly reversed the increased permeability for the paracellular route, whereas the normal rate of transcytosis was restored only in penetrating arterioles. We suggest that modulation of the apoM signaling axis may be clinically relevant, but heterogeneous responses of distinct vessel types to apoM shortage and S1PR1 agonist treatment should be taken into account in the development of protective strategies in neurological conditions.

Understanding the influence of blood-borne signaling molecules on brain endothelial cells is critical for an understanding of the BBB function. We report that lack of apoM increased the BBB permeability for small molecules without changes in size, structure, magnitude, or subcellular localization of tight junction complexes. Furthermore, we report an up to 10–fold increase in adsorptive transcytosis in the endothelial cells of pial and penetrating arterioles, but not in venules and capillaries. Thus, ApoM modulates the flux of small and large molecules to different extents in different vascular segments. Finally, the increased BBB permeability for small molecules and transcytosis-mediated large proteins could be rescued by selective stimulation of the S1PR1. So far, the two-photon assessments of the BBB in vivo are scarce. The presented data is first to show the heterogeneity of the BBB responses to S1PR1 impairment and treatment in different vessel types, thus underlines the necessity of studying the BBB in a living brain with respect to different functional and anatomical regions of the microvascular tree. This may be of particular importance in clinical research as S1PR1 modulation is currently used in FDA-approved therapies in humans (Brinkmann et al., 2010).

From among the exogenous tracers typically used in BBB paracellular permeability studies, we chose three molecules with different sizes, NaFluo and Alexa Fluor 488 that readily diffuse via the BBB, and FITC-dextran that has low BBB permeability (Shi et al., 2014; Kutuzov et al., 2018).

The loss of BBB integrity in Apom^-/- mice was observed for small tracer molecules < 0.7 kDa, but no significant leak was observed for 10 kDa dextran, which is in accordance with previous findings in S1PR1–knock-out mice (Yanagida et al., 2017). However, in contrast to Yanagida and colleagues (Yanagida et al., 2017), we show that it is not the complete absence of brain endothelial S1PR1 signaling, but a lack of a specific fraction of S1P circulating in the blood (i.e., apoM-bound S1P) is sufficient to impair the BBB, and occurs despite the presence of active S1PR1 (Christoffersen et al., 2011). Although we cannot exclude that some NaFluo molecules were entrapped in transport vesicles during their formation at the luminal side of the endothelium, in our experiments we did not detect any vesicular fraction of NaFluo, Alexa Fluor 488 and FITC-dx at the BBB. In contrast, albumin-conjugated Alexa 488 showed clear vesicular pattern, which is consistent with transcytosis (De Bock et al., 2016; Minshall et al., 2000; Minshall et al., 2002). Furthermore, NaFluo is a strong target for endothelium efflux pumps, that is multidrug resistance proteins (MRP) that sequester the tracer back to the blood stream (Hawkins et al., 2007). Therefore, we consider that the incidental transcytosis of NaFluo, Alexa Fluor 488 or FITC-dx had negligible contribution to fluorescence increases, and the effect observed in the brain parenchyma occurred due to the increase in paracellular permeability.

The increased permeability along the paracellular pathway occurs most commonly in response to severe damage (Farrell and Shivers, 1984; Houthoff et al., 1982; Lossinsky et al., 1995) and is typically reported to be secondary to the ultrastructural abnormalities of junctional complexes, such as truncated morphology during acute BBB breakdown, for example in stroke, sepsis, and brain tumors (Davies, 2002; Engelhardt et al., 2014; Knowland et al., 2014); and in diabetes (Salameh et al., 2016). S1P has been previously shown as an endothelial barrier-enhancing molecule in the lungs (Schaphorst et al., 2003; Dudek and Garcia, 2001; Garcia et al., 2001) and recently, in the brain (Yanagida et al., 2017; Swendeman et al., 2017). Our data ties apoM shortage-induced increase in BBB permeability with S1PR1. The mechanisms of S1PR1-mediated protective effect are not yet fully understood, but may be linked with Rho superfamily of small GTPases. Stimulation of S1PR1 and S1PR2 activates preferentially Rac and Rho, respectively, whilst S1PR3 stimulation activates both GTPases (Xiong and Hla, 2014; Windh et al., 1999). Rac and Rho modulate cytoskeleton dynamics in various cell types (Burridge and Wennerberg, 2004), including the formation and maintenance of a cortical actin ring that stabilizes intercellular junctions between adjoining endothelial cells (Garcia et al., 2001; McVerry and Garcia, 2004). At physiological concentrations, S1P activates preferentially Rac via S1PR1 over Rho (Garcia et al., 2001; Shikata et al., 2003; Hla, 2003), which causes a redistribution of proteins that facilitate cortical actin ring assembly, and consequently tightening of the barrier (Garcia et al., 2001; Mehta et al., 2005). Inhibition of Rac downstream of S1PR1 leads to actin depolymerization, formation of F-actin stress fibers and increased permeability (Wójciak-Stothard et al., 2001; Singleton et al., 2005), and S1PR2 causes Rho activation that inhibits Rac (Dudek and Garcia, 2001; Hla, 2003). However, the formation and disassembly of actin cortical ring affecting BBB permeability should not be simply viewed as Rac vs. Rho antagonism, as inhibition of Rho, similarly to Rac, can reportedly also increase barrier permeability, although without interrupting the actin ring assembly (Garcia et al., 2001; Etienne-Manneville and Hall, 2002). Our quantitative TEM assessment shows that apoM deficiency did not induce changes in junctional complexes ultrastructure. This suggests that the increase of the BBB permeability in Apom^-/- mice was either uncoupled from cortical actin ring remodeling, or that during S1PR1 hypostimulation and ongoing S1PR2-mediated Rho inhibition of Rac, the activity of Rac was still sufficient to maintain the elements of scaffolding complex of cortical actin ring that stabilize junctional complexes.

The small (~10%) increase in endothelium thickness in Apom^-/- mice may be due to the impaired S1PR1 -dependent formation and the maintenance of the cortical actin ring; and formation of actin stress fibers facilitated by S1PR2 activation (Garcia et al., 2001; Mehta et al., 2005; Wójciak-Stothard et al., 2001; Singleton et al., 2005). Indirectly, BBB permeability changes may be due to osmotic imbalance and cell swelling, but it is uncertain whether this occurs in the brains of Apom^-/- mice. Lack of S1PR1 activation aggravates edema in acute brain and lung injury (Ito, 2019), but here the system may not be challenged enough to induce osmotic swelling, as Apom^-/- mice have no signs of lung edema and exhibit normal microvasculature morphology (Christoffersen et al., 2011). Other processes may also influence endothelium thickness, but their relevance in Apom^-/- mice is yet to be established. For example, S1PR1 activity counteracts vascular endothelial growth factor (VEGF) -mediated endothelium contraction in angiogenesis (Gaengel et al., 2012), but whether S1PR1 hypostimulation affects VEGF signaling in the adult brain in Apom^-/- mice is unknown. In addition, impaired S1PR1 signaling activates neuroinflammatory factors (Blaho and Hla, 2014; Blaho et al., 2015), and for example TNF-alpha has been shown to alter cytoskeleton and hyperplastic properties of endothelial cells (Kang et al., 2008; Stroka and Aranda-Espinoza, 2011). Thus, it cannot be excluded, that the changes in endothelium morphology result from both: direct effect of S1PR1 hypostimulation on endothelial cell, and indirect effects linked with impaired BBB-induced loss of brain homeostasis.

Notably, a significant increase in paracellular permeability without apparent changes in junctional complex morphology has been observed by others following osmotic shock (Farrell and Shivers, 1984) and in claudin-5-deficient mice (Nitta et al., 2003). The loss of BBB integrity in Apom^-/- mice appeared to be to a lesser extent than in acute pathology (e.g., traumatic brain injury or ischemic stroke), as the BBB permeability towards 10 kDa dextran did not increase in Apom^-/- mice (Habgood et al., 2007; Özen et al., 2018). Yet, even with is morphology intact, the BBB with a persistent increase in permeability may still contribute to brain pathology (Carvey et al., 2009).

Our in vivo results characterize apoM as a blood-borne molecule that can affect the BBB permeability via S1PR1. In inflammatory conditions, elevated concentrations of blood-circulating thrombin activate protease-activated receptor-1 (PAR1), and subsequently barrier-disruptive metalloproteinases (Bogatcheva et al., 2002; Rempe et al., 2016). On the contrary, low thrombin concentrations activate protein C (APC), a substrate for endothelial cell protein C receptor (EPCR), which alters PAR1 signaling to promote the synthesis of S1P via Sphk-1, and facilitates barrier enhancement (Riewald et al., 2002; Feistritzer and Riewald, 2005). In addition, APC has been shown to also induce S1PR1 phosphorylation, which further promotes the S1PR1 signaling branch in the endothelium (Lee et al., 2001). In line with our results in Apom^-/- mice, the barrier enhancement by blood-borne thrombin occurred via S1PR1, as silencing of S1PR1 but not e.g. S1PR3 abolished the APC-mediated effect (Feistritzer and Riewald, 2005; Finigan et al., 2005). Except for apoM and thrombin, S1P signaling can be modulated by hyaluronic acid (HA). Depending on the form, i.e. high-molecular weight-HA (HMW-HA) or low-molecular weight (LMW-HA), the complex promotes interaction of a cell-surface glycoprotein CD44 isoforms with either S1PR1 or S1PR1/3, respectively (Singleton et al., 2006). This leads to enhancement of the barrier function via S1PR1 or an increase in BBB permeability via S1PR3 due to transactivation (i.e. phosphorylation) of respective receptors by CD44 isoforms, independently of S1P levels (Singleton et al., 2006). This further corroborates our findings on the regulation of S1P signaling by blood circulating molecules via preferential activation of specific S1P receptors.

However, the analogies should be made with caution, as the mechanistic insights come primarily from in vitro barrier models or non-brain tissue, where endothelial barrier properties may differ from the BBB in vivo. For example, Rac and Rho are known to elicit cell-type and subcellular localization-specific effects (Burridge and Wennerberg, 2004; McVerry and Garcia, 2004; Donati and Bruni, 2006), and their intracellular pathways are cross-linked with numerous regulatory feedback loops, including for example Rho inhibiting Rac and vice versa (Burridge and Wennerberg, 2004; Sander et al., 1999). This adds to the complexity of interpretation of Apom knock-out effects on the BBB and is currently an active area in research.

The hypostimulation of S1PR1 in Apom^-/- mice is likely to shift the signaling equilibrium towards cellular pathways that promote activation of Rho (via S1PR2) over Rac (via S1PR1), and the effects of increased BBB permeability are likely to be the net outcome of the failure in homeostatic interplay between receptor-dependent branches of S1P signaling, rather than simply a decrease in Rac activity. Consequently, the observed impairment of the BBB cannot simply be linked to a reduction in the amount of circulating S1P, but more specifically to the lack of apoM-bound S1P in favor of albumin-bound S1P in the blood. This notion is further supported by the result of the selective stimulation of S1PR1, which restored the BBB permeability in Apom^-/- mice to the level of healthy controls.

Given that inhibition of S1PR2 tightens the endothelial barrier in lungs by facilitating cortical actin ring assembly and stabilization of tight junctions (Sanchez et al., 2007), and in the brain supports the BBB functional integrity (Kim et al., 2015; Cao et al., 2019), it is plausible that S1PR2 stimulation may alleviate BBB phenotype in Apom^-/- mice. It should be noted, however, that S1PR1 expression in the endothelium is higher in the arterial branch of cerebral vasculature compared to venules, whereas S1PR2 expression is higher in venules than in arterioles (Vanlandewijck et al., 2018). It may lead, similar as in SEW2871 treatment, to region-specific effects, where the BBB responses to S1PR2 modulation may differ between distinct types of cerebral microvessels.

Though paracellular permeability restriction is typically viewed as the main functional constituent of the BBB, the low prevalence of transcytosis is equally important for preservation of the brain microenvironment (Knowland et al., 2014; Habgood et al., 2007; Hashizume and Black, 2002; Krueger et al., 2013). Recently, Mfsd2a was identified as a critical protein in the suppression of transcytosis. Similar to Apom^-/-, a lack of Mfsd2a leads to an increase in vesicular transport across the endothelium that compromises the BBB without structurally opening the paracellular route (Ben-Zvi et al., 2014) or changing junctional protein composition (Yang et al., 2017). Furthermore, the increase in BBB permeability can occur via both the transcellular and paracellular routes, but at different time points; e.g. the increase in transcytosis rate can precede paracellular leakage in stroke (Knowland et al., 2014), and selective dysregulation of the transcellular pathway can occur while the tight junctions are preserved (Krueger et al., 2013). Thus, the intact morphology of junctional complexes, as shown here, is not necessarily indicative of preserved BBB properties.

Noteworthy, the lack of apoM-S1P lead to an increased rate of transcytosis, though only in pial and penetrating arterioles. The susceptibility of the arterial branch of the microvasculature to apoM shortage may be linked to preferential expression of S1PR1 and APC in pial and penetrating arterioles (Vanlandewijck et al., 2018), thus possibly high reliance in these vessel types on S1PR1 signaling in the maintenance of the BBB. It is unclear, however, why penetrating, but not pial arterioles responded to SEW2871, but anatomical differences may be of importance. For example, S1P signaling promotes the formation of the glycocalyx, which limits the diffusion of hydrophilic and negatively charged substances, and supports the barrier function (Zhang et al., 2016). Glycocalyx in pial arterioles is estimated to be thicker compared to the penetrating arterioles (Yoon et al., 2017), but it is unknown how S1PR1 hypostimulation affects distribution and coverage of glycocalyx layer in Apom^-/- mice. In addition, the reconstitution of barrier function may have a different time course in pial and penetrating arterioles. Lastly, in contrast to bolus SEW2871 injection, a sustained stimulation of S1PR1 may be needed to restore BBB function in pial arterioles during ongoing apoM deficit.

High-density lipoprotein (HDL) particles are heterogeneous in size and content of apolipoproteins and lipids. In humans, HDL plasma concentrations correlate with reduced susceptibility to cerebro- and cardiovascular diseases (Rader and Tall, 2012; Hovingh et al., 2015; Fellows et al., 2015), and approximately 5% of HDL contains apoM (Xu and Dahlbäck, 1999; Christoffersen et al., 2006). The beneficial effects of HDL can be, in part, explained by HDL association to apoM/S1P. We show that lack of apoM increases the flux of small molecules across the BBB, similar to previous findings investigating the permeability in lung and adipose tissue (Christoffersen et al., 2011; Christensen et al., 2016; Christoffersen et al., 2018). Stressing the system even further, lack of apoM increases the susceptibility to neuroinflammation (Blaho et al., 2015; Galvani et al., 2015). Mainly this has been interpreted as effects caused by blood-circulating apoM/S1P complex. However, a recent study suggested that porcine brain endothelial cells express and secrete apoM into the brain parenchyma (Kober et al., 2017). This has not been reported in other species but could also play a role in the increased permeability observed in the present study. Except S1P, apoM can potentially bind other ligands, for example retinoic acid (Ahnström et al., 2007) or oxidized phospholipids (Elsøe et al., 2012). Lack of apoM would increase free oxidized phospholipid content, which potentially can also affect the BBB (Singleton et al., 2009). However, reversing the BBB phenotype by SEW2871 suggests that the observed effects are primarily mediated via S1PR1 rather than for example oxidized phospholipids. Noteworthy, with the absence of apoM, S1P may still associate to HDL. A recent study showed that in mice lacking expression of both, apoM and albumin, S1P binds to HDL via novel S1P binding protein apoA4 (Obinata et al., 2019). This may potentially constitute a compensatory mechanism in Apom^-/- mice, but whether HDL/apoA4/S1P complex also plays a role in maintaining the BBB is unknown and will need further investigations.

Two-photon imaging allows studying the endothelial barrier in the living brain with all its structural and functional constituents, including blood flow, and at the resolution of single microvessels. However, like any imaging approach, it has also limitations that apply to our study. In contrast to transcellular vesicular transport, the fast diffusion of NaFluo in the brain parenchyma made it not feasible to analyze for differences in paracellular permeability increase between distinct vessel types in Apom^-/- mice. Regarding the transcellular permeability assessment, we have only investigated the transcytosis of albumin, which represents a fraction of receptor-mediated transcellular pathways. Lastly, the surgical procedures might also affect the brain physiology, however in our previous works, we observed no significant effects of cranial window preparation and imaging on the neurovascular coupling, neuronal and astrocytic calcium transients, electrophysiological activity and cell morphology, suggesting lack of effects on the brain that could significantly affect the BBB function (Kutuzov et al., 2018; Kucharz and Lauritzen, 2018; Hall et al., 2014). Instead of acute craniotomy, further studies may employ chronic window imaging to address changes in BBB permeability in Apom^-/- mice over a longer time.

In summary, apoM is critical for maintaining low paracellular and transcellular permeability at the BBB. The BBB is heterogeneous in the susceptibility towards apoM shortage and in the potential for rescue mediated by the S1PR1 signaling pathway. The pronounced increase in transcytosis in Apom^-/- mice stresses the importance of considering the development of protective strategies for this pathway to regulate the immediate microenvironment of brain cells and reduce secondary neural damage in both acute and chronic neurological conditions.

Dataset has been deposited at Dryad Digital Repository: https://doi.org/10.5061/dryad.qg04542.

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Author details

1. Mette Mathiesen Janiurek

   Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark

   Contribution

   Data curation, Formal analysis, Validation, Investigation, Visualization, Writing—original draft

   Competing interests

   No competing interests declared

2. Rana Soylu-Kucharz

   Department of Experimental Medical Science, Lund University, Lund, Sweden

   Contribution

   Resources, Validation, Investigation, Visualization, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

3. Christina Christoffersen

   1. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
   2. Department of Biomedical Sciences, Copenhagen University, Copenhagen, Denmark

   Contribution

   Resources, Investigation, Writing—review and editing

   Competing interests

   No competing interests declared

4. Krzysztof Kucharz

   Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark

   Contribution

   Conceptualization, Formal analysis, Supervision, Validation, Investigation, Visualization, Methodology, Writing—original draft, Writing—review and editing

   Contributed equally with

   Martin Lauritzen

   For correspondence

   kucharz@sund.ku.dk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6852-5300

5. Martin Lauritzen

   1. Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark
   2. Department of Clinical Neurophysiology, Rigshospitalet-Glostrup, Copenhagen, Denmark

   Contribution

   Conceptualization, Supervision, Funding acquisition, Writing—original draft, Project administration, Writing—review and editing

   Contributed equally with

   Krzysztof Kucharz

   For correspondence

   mlauritz@sund.ku.dk

   Competing interests

   No competing interests declared

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