scholarly journals Apolipoprotein M-bound sphingosine-1-phosphate regulates blood–brain barrier paracellular permeability and transcytosis

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Mette Mathiesen Janiurek ◽  
Rana Soylu-Kucharz ◽  
Christina Christoffersen ◽  
Krzysztof Kucharz ◽  
Martin Lauritzen
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Sodium Fluorescein ◽  
Cerebral Microvessels ◽  
Apolipoprotein M ◽  
Two Photon Microscopy ◽  
Blood Brain ◽  
Sphingosine 1 Phosphate ◽  
Pial Arterioles ◽  
Bbb Permeability

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.

scholarly journals Apolipoprotein M-bound sphingosine-1-phosphate regulates blood-brain barrier paracellular permeability and transcytosis

2019 ◽  
Author(s):  
Mette Mathiesen Janiurek ◽  
Christina Christoffersen ◽  
Krzysztof Kucharz ◽  
Martin Lauritzen
Keyword(s):  
Endothelial Cells ◽  
Small Molecules ◽  
Blood Brain Barrier ◽  
Structural Changes ◽  
Brain Barrier ◽  
Cerebral Microvessels ◽  
Apolipoprotein M ◽  
Blood Brain ◽  
Sphingosine 1 Phosphate ◽  
Bbb Permeability

ABTRACTThe blood-brain barrier (BBB) is formed by the endothelial cells lining cerebral microvessels. Here, we report that the BBB permeability is modified by apolipoprotein M (apoM)-bound sphingosine 1-phosphate (S1P). We used two-photon microscopy to monitor changes in BBB permeability in apoM-deficient mice (apoM−/−), showing significant increases in paracellular BBB permeability to small molecules without structural changes in junctional complexes between endothelial cells. Lack of apoM-bound S1P increased vesicle-mediated transfer of albumin across endothelium of brain pial and penetrating arterioles, whereas transcytosis in capillaries and venules remained unchanged. S1PR1 agonist SEW2871 rapidly normalized BBB permeability along both the paracellular and transcellular routes in apoM−/− mice. Thus, apoM-bound S1P maintains low paracellular BBB permeability for small molecules in all cerebral microvessels and low levels of adsorptive transcytosis in penetrating arterioles. Modulation of apoM/S1P-dependent signaling may be a novel strategy for the protection of brain endothelial cells to preserve the BBB function.

Functional impairment of blood-brain barrier following pesticide exposure during early development in rats

1999 ◽  
Vol 18 (3) ◽  
pp. 174-179 ◽  
Author(s):  
Alka Gupta ◽  
Renu Agarwal ◽  
Girja S Shukla
Keyword(s):  
Blood Brain Barrier ◽  
Repeated Exposure ◽  
Neurological Dysfunction ◽  
Brain Barrier ◽  
Sodium Fluorescein ◽  
Rat Pups ◽  
Blood Brain ◽  
Brain Uptake Index ◽  
Old Rats ◽  
Bbb Permeability

1 The effect of certain pesticides on the functional integrity of the developing blood-brain barrier (BBB) was studied following single and repeated exposure, and after subsequent withdrawal in rats. 2 Ten-day-old rat pups exposed orally to quinalphos (QP, organophosphate), cypermethrin (CM, pyre-throid) and lindane (LD, organochlorine) at a dose of 1/50th of LD50, showed a significant increase in the brain uptake index (BUI) for a micromolecular tracer, sodium fluorescein (SF), by 97, 37 and 72%, respectively, after 2 h. Residual increases in the BUI were found even after 3 days of the single treatment of QP (28%) and LD (23%). 3 Repeated exposure for 8 days (postnatal days (PND) 10-17) with QP, CM and LD increased the BBB permeability by 130, 80 and 50%, respectively. Recovery from these changes was complete in QP and LD-treated animals after 13 days (PND 18-30) of withdrawal. However, CM showed persistent effects that were normalized only after 43 days (PND 18-60) of withdrawal. 4 A single dose reduced to 1/100th of LD50 also increased BUI in 10-day-old rat pups following QP (20%) and CM (28%) exposure at 2 h. 5 An age-dependent effect of these pesticides was evident from the study showing higher magnitude of BUI changes in 10-day-old rats as compared to that in 15- day-old rats. Furthermore, adult rats did not show any effect on BBB permeability even at a higher dose (1/25th of LD50) of these pesticides given alone or in combination with piperonyl butoxide (600 mg/kg, i.p.) for 3 consecutive days. 6 This study showed that developing BBB is highly vulnerable to single or repeated exposure of certain pesticides. The observed persistent effects during brain development even after withdrawal of the treatment may produce some neurological dysfunction at later life as well.

scholarly journals Endothelium-Macrophage Crosstalk Mediates Blood-Brain Barrier Dysfunction in Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (3) ◽  
pp. 795-807 ◽  
Author(s):  
Monica M. Santisteban ◽  
Sung Ji Ahn ◽  
Diane Lane ◽  
Giuseppe Faraco ◽  
Lidia Garcia-Bonilla ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Cooperative Interaction ◽  
Brain Barrier ◽  
Viral Gene ◽  
Ang Ii ◽  
Barrier Dysfunction ◽  
Cerebral Microvessels ◽  
Blood Brain ◽  
Bbb Permeability

Hypertension is a leading cause of stroke and dementia, effects attributed to disrupting delivery of blood flow to the brain. Hypertension also alters the blood-brain barrier (BBB), a critical component of brain health. Although endothelial cells are ultimately responsible for the BBB, the development and maintenance of the barrier properties depend on the interaction with other vascular-associated cells. However, it remains unclear if BBB disruption in hypertension requires cooperative interaction with other cells. Perivascular macrophages (PVM), innate immune cells closely associated with cerebral microvessels, have emerged as major contributors to neurovascular dysfunction. Using 2-photon microscopy in vivo and electron microscopy in a mouse model of Ang II (angiotensin II) hypertension, we found that the vascular segments most susceptible to increased BBB permeability are arterioles and venules >10 µm and not capillaries. Brain macrophage depletion with clodronate attenuates, but does not abolish, the increased BBB permeability in these arterioles where PVM are located. Deletion of AT1R (Ang II type-1 receptors) in PVM using bone marrow chimeras partially attenuated the BBB dysfunction through the free radical-producing enzyme Nox2. In contrast, downregulation of AT1R in cerebral endothelial cells using a viral gene transfer-based approach prevented the BBB disruption completely. The results indicate that while endothelial AT1R, mainly in arterioles and venules, initiate the BBB disruption in hypertension, PVM are required for the full expression of the dysfunction. The findings unveil a previously unappreciated contribution of resident brain macrophages to increased BBB permeability of hypertension and identify PVM as a putative therapeutic target in diseases associated with BBB dysfunction.

scholarly journals Increased blood–brain barrier permeability is not a primary determinant for lethality of West Nile virus infection in rodents

2008 ◽  
Vol 89 (2) ◽  
pp. 467-473 ◽  
Author(s):  
John D. Morrey ◽  
Aaron L. Olsen ◽  
Venkatraman Siddharthan ◽  
Neil E. Motter ◽  
Hong Wang ◽  
...  
Keyword(s):  
West Nile Virus ◽  
Blood Brain Barrier ◽  
Semliki Forest Virus ◽  
Brain Barrier ◽  
Sodium Fluorescein ◽  
West Nile ◽  
Blood Brain ◽  
Lethal Infection ◽  
Primary Determinant ◽  
Bbb Permeability

Blood–brain barrier (BBB) permeability was evaluated in mice and hamsters infected with West Nile virus (WNV, flavivirus) as compared to those infected with Semliki Forest (alphavirus) and Banzi (flavivirus) viruses. BBB permeability was determined by measurement of fluorescence in brain homogenates or cerebrospinal fluid (CSF) after intraperitoneal (i.p.) injection of sodium fluorescein, by macroscopic examination of brains after i.p. injection of Evans blue, or by measurement of total protein in CSF compared to serum. Lethal infection of BALB/c mice with Semliki Forest virus and Banzi virus caused the brain : serum fluorescence ratios to increase from a baseline of 2–4 % to as high as 11 and 15 %, respectively. Lethal infection of BALB/c mice with WNV did not increase BBB permeability. When C57BL/6 mice were used, BBB permeability was increased in some, but not all, of the WNV-infected animals. A procedure was developed to measure BBB permeability in live WNV-infected hamsters by comparing the fluorescence in the CSF, aspirated from the cisterna magnum, with the fluorescence in the serum. Despite a time-dependent tendency towards increased BBB permeability in some WNV-infected hamsters, the highest BBB permeability values did not correlate with mortality. These data indicated that a measurable increase in BBB permeability was not a primary determinant for lethality of WNV infection in rodents. The lack of a consistent increase in BBB permeability in WNV-infected rodents has implications for the understanding of viral entry, viral pathogenesis and accessibility of the CNS of rodents to drugs or effector molecules.

scholarly journals Region-specific disruption of the blood-brain barrier following repeated inflammatory dural stimulation in a rat model of chronic trigeminal allodynia

Cephalalgia ◽  
2017 ◽  
Vol 38 (4) ◽  
pp. 674-689 ◽  
Author(s):  
Nathan T Fried ◽  
Christina R Maxwell ◽  
Melanie B Elliott ◽  
Michael L Oshinsky
Keyword(s):  
Blood Brain Barrier ◽  
Rat Model ◽  
Microglial Activation ◽  
Brain Regions ◽  
Brain Barrier ◽  
Sodium Fluorescein ◽  
Blood Brain ◽  
Bbb Permeability ◽  
The Impact ◽  
Trigeminal Sensitivity

Background The blood-brain barrier (BBB) has been hypothesized to play a role in migraine since the late 1970s. Despite this, limited investigation of the BBB in migraine has been conducted. We used the inflammatory soup rat model of trigeminal allodynia, which closely mimics chronic migraine, to determine the impact of repeated dural inflammatory stimulation on BBB permeability. Methods The sodium fluorescein BBB permeability assay was used in multiple brain regions (trigeminal nucleus caudalis (TNC), periaqueductal grey, frontal cortex, sub-cortex, and cortex directly below the area of dural activation) during the episodic and chronic stages of repeated inflammatory dural stimulation. Glial activation was assessed in the TNC via GFAP and OX42 immunoreactivity. Minocycline was tested for its ability to prevent BBB disruption and trigeminal sensitivity. Results No astrocyte or microglial activation was found during the episodic stage, but BBB permeability and trigeminal sensitivity were increased. Astrocyte and microglial activation, BBB permeability, and trigeminal sensitivity were increased during the chronic stage. These changes were only found in the TNC. Minocycline treatment prevented BBB permeability modulation and trigeminal sensitivity during the episodic and chronic stages. Discussion Modulation of BBB permeability occurs centrally within the TNC following repeated dural inflammatory stimulation and may play a role in migraine.

scholarly journals Effects of acute hypoxia and hyperthermia on the permeability of the blood-brain barrier in adult rats

2009 ◽  
Vol 107 (4) ◽  
pp. 1348-1356 ◽  
Author(s):  
Sirajedin S. Natah ◽  
Sathya Srinivasan ◽  
Quentin Pittman ◽  
Zonghang Zhao ◽  
Jeff F. Dunn
Keyword(s):  
High Altitude ◽  
Blood Brain Barrier ◽  
Vasogenic Edema ◽  
Acute Hypoxia ◽  
Acute Mountain Sickness ◽  
Brain Barrier ◽  
Adaptation To Hypoxia ◽  
Sodium Fluorescein ◽  
Blood Brain ◽  
Bbb Permeability

Acute mountain sickness (AMS) develops within a few hours after arrival at high altitude and includes headache, anorexia, nausea, vomiting, and malaise. This afflicts 15–25% of the general tourist population at moderate altitudes. High-altitude cerebral edema (HACE) is considered to be the end stage of severe AMS and has been suggested to be a vasogenic edema, raising the possibility that acute hypoxia may increase blood-brain barrier (BBB) permeability. At present, there are no good small-animal models to study this syndrome. We hypothesize 1) that acute hypoxia can damage the BBB and 2) that rat can be used as a model to study hypoxia-induced changes in BBB permeability, especially if hypoxia-induced hypothermia could be minimized with high ambient temperature (HAT). Male Wistar rats were exposed to 1, 2, and 7 days of hypobaric hypoxia (equivalent to 0.5 atm), and changes in the temperature and BBB permeability were studied. The extravasation of endogenous immunoglobulin G, a large molecule, did not increase during room temperature hypoxia but did increase when hypoxia was combined with HAT. Hypoxia caused a significant increase in the leakage of sodium fluorescein (mol wt 376 Da). The expression of endothelial barrier antigen (EBA), a protein associated with the BBB, was reduced to 50% between 24 and 48 h after exposure to hypoxia, and the loss was exacerbated by HAT. The values almost returned to control levels by 7 days, showing adaptation to hypoxia. Hypoxic rats exhibited sodium fluorescein leakage mainly in focal areas in the brain parenchyma. In conclusion, it is possible to have transient BBB damage through exposure to acute hypoxia, and this damage is exacerbated by increasing body temperature to more of a normothermic value.

scholarly journals C-Type Natriuretic Peptide Modulates Permeability of the Blood–Brain Barrier

2014 ◽  
Vol 34 (4) ◽  
pp. 589-596 ◽  
Author(s):  
Manoj Bohara ◽  
Yuki Kambe ◽  
Tetsuya Nagayama ◽  
Hiroshi Tokimura ◽  
Kazunori Arita ◽  
...  
Keyword(s):  
Natriuretic Peptide ◽  
Blood Brain Barrier ◽  
Messenger Rna ◽  
Brain Barrier ◽  
Sodium Fluorescein ◽  
Blood Brain ◽  
Protein Expressions ◽  
Bbb Permeability

C-type natriuretic peptide (CNP) is abundant in brain and is reported to exert autocrine function in vascular cells, but its effect on blood–brain barrier (BBB) permeability has not been clarified yet. Here, we examined this effect. Transendothelial electrical resistance (TEER) of in vitro BBB model, composed of bovine brain microvascular endothelial cells and astrocytes, was significantly dose dependently decreased by CNP (1, 10, and 100 nmol/L). C-type natriuretic peptide treatment reduced both the messenger RNA (mRNA) and protein expressions of tight junction (TJ) protein zonula occludens-1 (ZO-1). The effects on TEER, mRNA, and protein expressions of ZO-1 were mimicked by cyclic GMP (cGMP) analog 8-bromo-cGMP (1  μmol/L) and reversed by protein kinase G (PKG) inhibitor Rp-8-CPT-cGMPS (100  μmol/L), thus implying the role of PKG and cGMP signaling in BBB function. Transcription factor JunD knockdown by small interfering RNA resulted in no change of permeability by CNP. In vivo study of mouse brain by fluorimetric analysis with intravenous administration of sodium fluorescein (40 mg/kg) also showed a significant increase in BBB permeability by CNP (10 nmol/kg, intravenously). These findings suggest that CNP modulates the BBB permeability by altering ZO-1 expression.

scholarly journals TIMP-1 Attenuates Blood–Brain Barrier Permeability in Mice with Acute Liver Failure

2013 ◽  
Vol 33 (7) ◽  
pp. 1041-1049 ◽  
Author(s):  
Feng Chen ◽  
Evette S Radisky ◽  
Pritam Das ◽  
Jyotica Batra ◽  
Toshiyuki Hata ◽  
...  
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Blood Brain Barrier ◽  
Growth Factor Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Brain Barrier ◽  
Sodium Fluorescein ◽  
Blood Brain ◽  
Junction Protein ◽  
Bbb Permeability

Blood-brain barrier (BBB) dysfunction in acute liver failure (ALF) results in increased BBB permeability that often precludes the patients from obtaining a life-saving liver transplantation. It remains controversial whether matrix metalloproteinase-9 (MMP-9) from the injured liver contributes to the deregulation of BBB function in ALF. We selectively upregulated a physiologic inhibitor of MMP-9 (TIMP-1) with a single intracerebroventricular injection of TIMP-1 cDNA plasmids at 48 and 72 hours, or with pegylated-TIMP-1 protein. Acute liver failure was induced with tumor necrosis factor-α and D-(+)-galactosamine in mice. Permeability of BBB was assessed with sodium fluorescein (NaF) extravasation. We found a significant increase in TIMP-1 within the central nervous system (CNS) after the administration of TIMP-1 cDNA plasmids and that increased TIMP-1 within the CNS resulted in an attenuation of BBB permeability, a reduction in activation of epidermal growth factor receptor and p38 mitogen-activated protein kinase signals, and a restoration of the tight junction protein occludin in mice with experimental ALF. Pegylated TIMP-1 provided similar protection against BBB permeability in mice with ALF. Our results provided a proof of principle that MMP-9 contributes to the BBB dysfunction in ALF and suggests a potential therapeutic role of TIMP-1 in ALF.

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