Junctional proteins of the blood-brain barrier: New insights into function and dysfunction

Stamatovic, Svetlana M.; Johnson, Allison M.; Keep, Richard F.; Andjelkovic, Anuska V.

doi:10.1080/21688370.2016.1154641

Cited by 317 publications

(261 citation statements)

References 152 publications

(215 reference statements)

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“…VE-Cadherin has an intimate relation to the VEGFR and is a major control point for regulation of barrier development, paracellular permeability and growth control but a detailed discussion is beyond this review. (For more information on adherens junctions in paracellular barrier refer to reviews (Bazzoni and Dejana 2004, Giannotta, Trani et al 2013, Stamatovic, Johnson et al 2016)).…”

Section: Flux Across the Ibrbmentioning

confidence: 99%

The inner blood-retinal barrier: Cellular basis and development

2017

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Section: Flux Across the Ibrbmentioning

confidence: 99%

The inner blood-retinal barrier: Cellular basis and development

2017

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“…It is well established that tight regulation of the endothelial barrier is required to limit fluid exchange with the surrounding tissue and that endothelial barrier breakdown contributes to multi‐organ failure in inflammation . During the last decade, our understanding on the mechanisms regulating the endothelial barrier has broadened significantly and a number of review articles have been released to cover this field: from articles focusing on the structure of the barrier and the role of actin dynamics some with particular focus on the blood–brain barrier to mechanisms engaged by leucocytes to cross the endothelium . Similarly, the signalling pathways controlling the barrier and especially the roles of Rho GTPases and cAMP have been described in detail .…”

mentioning

confidence: 99%

Mind the gap: mechanisms regulating the endothelial barrier

2017

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The endothelial barrier consists of intercellular contacts localized in the cleft between endothelial cells, which is covered by the glycocalyx in a sievelike manner. Both types of barrier-forming junctions, i.e. the adherens junction (AJ) serving mechanical anchorage and mechanotransduction and the tight junction (TJ) sealing the intercellular space to limit paracellular permeability, are tethered to the actin cytoskeleton. Under resting conditions, the endothelium thereby builds a selective layer controlling the exchange of fluid and solutes with the surrounding tissue. However, in the situation of an inflammatory response such as in anaphylaxis or sepsis intercellular contacts disintegrate in post-capillary venules leading to intercellular gap formation. The resulting oedema can cause shock and multi-organ failure. Therefore, maintenance as well as coordinated opening and closure of interendothelial junctions is tightly regulated. The two principle underlying mechanisms comprise spatiotemporal activity control of the small GTPases Rac1 and RhoA and the balance of the phosphorylation state of AJ proteins. In the resting state, junctional Rac1 and RhoA activity is enhanced by junctional components, actin-binding proteins, cAMP signalling and extracellular cues such as sphingosine-1-phosphate (S1P) and angiopoietin-1 (Ang-1). In addition, phosphorylation of AJ components is prevented by junction-associated phosphatases including vascular endothelial protein tyrosine phosphatase (VE-PTP). In contrast, inflammatory mediators inhibiting cAMP/Rac1 signalling cause strong activation of RhoA and induce AJ phosphorylation finally leading to endocytosis and cleavage of VE-cadherin. This results in dissolution of TJs the outcome of which is endothelial barrier breakdown.

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“…TJs consist of different proteins such as membrane-spanning proteins from the claudin family and scaffolding proteins from the zonula occludens (ZO) family. In endothelial cells, the amino-terminal region of ZO-1 physically interacts with claudin 5 while its carboxy-terminal domain binds to cortactin and actin, thus bridging the TJ to intracellular cytoskeleton (Stamatovic, Johnson, Keep, & Andjelkovic, 2016). Although ZO proteins predominantly localize at cell-cell contacts, they can be redistributed to other cellular compartments such as nuclei during the wound-healing process (Gottardi, Arpin, Fanning, & Louvard, 1996).…”

Section: Introductionmentioning

confidence: 99%

Podosome formation impairs endothelial barrier function by sequestering zonula occludens proteins

Rui

Chen

Guo

et al. 2019

Journal Cellular Physiology

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Podosomes and tight junctions (TJs) are subcellular compartments that both exist in endothelial cells and localize at cell surfaces. In contrast to the well-characterized role of TJs in maintaining cerebrovascular integrity, the specific function of endothelial podosomes remains unknown. Intriguingly, we discovered cross-talk between podosomes and TJs in human brain endothelial cells. Tight junction scaffold proteins ZO-1 and ZO-2 localize at podosomes in response to phorbol-12-myristate-13-acetate treatment. We found that both ZO proteins are essential for podosome formation and function. Rather than being derived from new protein synthesis, podosomal ZO-1 and ZO-2 are relocated from a pre-existing pool found at the peripheral plasma membrane with enhanced physical interaction with cortactin, a known protein marker for podosomes. Sequestration of ZO proteins in podosomes weakens tight junction complex formation, leading to increased endothelial cell permeability. This effect can be further attenuated by podosome inhibitor PP2.Altogether, our data revealed a novel cellular function of podosomes, specifically, their ability to negatively regulate tight junction and endothelial barrier integrity, which have been linked to a variety of cerebrovascular diseases.

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Junctional proteins of the blood-brain barrier: New insights into function and dysfunction

Cited by 317 publications

References 152 publications

The inner blood-retinal barrier: Cellular basis and development

The inner blood-retinal barrier: Cellular basis and development

Mind the gap: mechanisms regulating the endothelial barrier

Podosome formation impairs endothelial barrier function by sequestering zonula occludens proteins

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