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.

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 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.

Potential Regulation Mechanisms of P-gp in the Blood-Brain Barrier in Hypoxia

2019 ◽  
Vol 25 (10) ◽  
pp. 1041-1051 ◽  
Author(s):  
Yidan Ding ◽  
Rong Wang ◽  
Jianchun Zhang ◽  
Anpeng Zhao ◽  
Hui Lu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Brain Tissue ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Signal Pathways ◽  
Blood Brain ◽  
Sphingosine 1 Phosphate ◽  
Capillary Endothelial Cells ◽  
The Brain ◽  
Expression And Activity

The blood-brain barrier (BBB) is a barrier of the central nervous system (CNS), which can restrict the free exchange of substances, such as toxins and drugs, between cerebral interstitial fluid and blood, keeping the relative physiological stabilization. The brain capillary endothelial cells, one of the structures of the BBB, have a variety of ATP-binding cassette transporters (ABC transporters), among which the most widely investigated is Pglycoprotein (P-gp) that can efflux numerous substances out of the brain. The expression and activity of P-gp are regulated by various signal pathways, including tumor necrosis factor-α (TNF-α)/protein kinase C-β (PKC- β)/sphingosine-1-phosphate receptor 1 (S1P), vascular endothelial growth factor (VEGF)/Src kinase, etc. However, it remains unclear how hypoxic signaling pathways regulate the expression and activity of P-gp in brain microvascular endothelial cells. According to previous research, hypoxia affects the expression and activity of the transporter. If the transporter is up-regulated, some drugs enter the brain's endothelial cells and are pumped back into the blood by transporters such as P-gp before they enter the brain tissue, consequently influencing the drug delivery in CNS; if the transporter is down-regulated, the centrally toxic drug would enter the brain tissue and cause serious adverse reactions. Therefore, studying the mechanism of hypoxia-regulating P-gp can provide an important reference for the treatment of CNS diseases with a hypoxia/reoxygenation (H/R) component. This article summarized the mechanism of regulation of P-gp in BBB in normoxia and explored that of hypoxia.

scholarly journals Role of Intermediate Filaments in Blood–Brain Barrier in Health and Disease

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1400
Author(s):  
Ece Bayir ◽  
Aylin Sendemir
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Intermediate Filaments ◽  
Intermediate Filament ◽  
Cell Junctions ◽  
Brain Barrier ◽  
Blood Brain ◽  
Health And Disease ◽  
Bbb Permeability ◽  
Cell Cell

The blood–brain barrier (BBB) is a highly selective cellular monolayer unique to the microvasculature of the central nervous system (CNS), and it mediates the communication of the CNS with the rest of the body by regulating the passage of molecules into the CNS microenvironment. Limitation of passage of substances through the BBB is mainly due to tight junctions (TJ) and adherens junctions (AJ) between brain microvascular endothelial cells. The importance of actin filaments and microtubules in establishing and maintaining TJs and AJs has been indicated; however, recent studies have shown that intermediate filaments are also important in the formation and function of cell–cell junctions. The most common intermediate filament protein in endothelial cells is vimentin. Vimentin plays a role in blood–brain barrier permeability in both cell–cell and cell–matrix interactions by affecting the actin and microtubule reorganization and by binding directly to VE-cadherin or integrin proteins. The BBB permeability increases due to the formation of stress fibers and the disruption of VE–cadherin interactions between two neighboring cells in various diseases, disrupting the fiber network of intermediate filament vimentin in different ways. Intermediate filaments may be long ignored key targets in regulation of BBB permeability in health and disease.

scholarly journals Protein S controls hypoxic/ischemic blood-brain barrier disruption through the TAM receptor Tyro3 and sphingosine 1-phosphate receptor

Blood ◽  
2010 ◽  
Vol 115 (23) ◽  
pp. 4963-4972 ◽  
Author(s):  
Donghui Zhu ◽  
Yaoming Wang ◽  
Itender Singh ◽  
Robert D. Bell ◽  
Rashid Deane ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Protein S ◽  
Glucose Deprivation ◽  
Brain Barrier ◽  
Brain Endothelial Cells ◽  
Blood Brain ◽  
Mouse Brain Endothelial Cells ◽  
Sphingosine 1 Phosphate

Abstract The anticoagulant factor protein S (PS) has direct cellular activities. Lack of PS in mice causes lethal coagulopathy, ischemic/thrombotic injuries, vascular dysgenesis, and blood-brain barrier (BBB) disruption with intracerebral hemorrhages. Thus, we hypothesized that PS maintains and/or enhances the BBB integrity. Using a BBB model with human brain endothelial cells, we show PS inhibits time- and dose-dependently (half maximal effective concentration [EC50] = 27 ± 3 nM) oxygen/glucose deprivation-induced BBB breakdown, as demonstrated by measurements of the transmonolayer electrical resistance, permeability of endothelial monolayers to dextran (40 kDa), and rearrangement of F-actin toward the cortical cytoskeletal ring. Using Tyro-3, Axl, and Mer (TAM) receptor, tyrosine kinase silencing through RNA interference, specific N-terminus–blocking antibodies, Tyro3 phosphorylation, and Tyro3-, Axl- and Mer-deficient mouse brain endothelial cells, we show that Tyro3 mediates PS vasculoprotection. After Tyro3 ligation, PS activated sphingosine 1-phosphate receptor (S1P1), resulting in Rac1-dependent BBB protection. Using 2-photon in vivo imaging, we show that PS blocks postischemic BBB disruption in Tyro3+/+, Axl−/−, and Mer−/− mice, but not in Tyro3−/− mice or Tyro3+/+ mice receiving low-dose W146, a S1P1-specific antagonist. Our findings indicate that PS protects the BBB integrity via Tyro3 and S1P1, suggesting potentially novel treatments for neurovascular dysfunction resulting from hypoxic/ischemic BBB damage.

scholarly journals Activation of Frizzled-7 attenuates blood–brain barrier disruption through Dvl/β-catenin/WISP1 signaling pathway after intracerebral hemorrhage in mice

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Wei He ◽  
Qin Lu ◽  
Prativa Sherchan ◽  
Lei Huang ◽  
Xin Hu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Intracerebral Hemorrhage ◽  
Signaling Pathway ◽  
Brain Edema ◽  
Blood Brain Barrier ◽  
Neurological Function ◽  
Brain Barrier ◽  
Secondary Brain Injury ◽  
Blood Brain ◽  
Bbb Permeability

Abstract Background Destruction of blood–brain barrier (BBB) ​​is one of the main mechanisms of secondary brain injury following intracerebral hemorrhage (ICH). Frizzled-7 is a key protein expressed on the surface of endothelial cells that controls vascular permeability through the Wnt-canonical pathway involving WNT1-inducible signaling pathway protein 1 (WISPI). This study aimed to investigate the role of Frizzled-7 signaling in BBB preservation after ICH in mice. Methods Adult CD1 mice were subjected to sham surgery or collagenase-induced ICH. Frizzled-7 activation or knockdown was performed by administration of Clustered Regularly Interspaced Palindromic Repeats (CRISPR) by intracerebroventricular injection at 48 h before ICH induction. WISP1 activation or WISP1 knockdown was performed to evaluate the underlying signaling pathway. Post-ICH assessments included neurobehavior, brain edema, BBB permeability, hemoglobin level, western blot and immunofluorescence. Results The brain expressions of Frizzled-7 and WISP1 significantly increased post-ICH. Frizzled-7 was expressed in endothelial cells, astrocytes, and neurons after ICH. Activation of Frizzled-7 significantly improved neurological function, reduced brain water content and attenuated BBB permeability to large molecular weight substances after ICH. Whereas, knockdown of Frizzled-7 worsened neurological function and brain edema after ICH. Activation of Frizzled-7 significantly increased the expressions of Dvl, β-Catenin, WISP1, VE-Cadherin, Claudin-5, ZO-1 and reduced the expression of phospho-β-Catenin. WISP1 knockdown abolished the effects of Frizzled-7 activation on the expressions of VE-Cadherin, Claudin-5 and ZO-1 at 24 h after ICH. Conclusions Frizzled-7 activation potentially attenuated BBB permeability and improved neurological deficits after ICH through Dvl​​/β-Catenin/WISP1 pathway. Frizzled-7 may be a potential target for the development of ICH therapeutic drugs.

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