Functional and morphological studies of protein transcytosis in continuous endothelia

Predescu, Dan; Vogel, Stephen M.; Malik, Asrar B.

doi:10.1152/ajplung.00075.2004

Cited by 92 publications

(80 citation statements)

References 50 publications

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“…In absence of a pathological insult, these junctions are normally impermeable to albumin and other plasma proteins. Electron micrographic studies have shown that this pathway is closed (restricted) and excludes macromolecule tracers [53][54][55][56][57]. The transport of albumin and other macromolecules across the endothelium under non-inflammatory physiological conditions can be fully explained by transcytosis involving the plasma membrane vesicular structures or caveolae [54,58].…”

Section: Src Family Kinase Signaling In Vascular Endothelial Permeabimentioning

confidence: 99%

Regulation of endothelial permeability by Src kinase signaling: Vascular leakage versus transcellular transport of drugs and macromolecules

Place

Minshall

2008

Chemico-Biological Interactions

102

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An important function of the endothelium is to regulate the transport of liquid and solutes across the semi-permeable vascular endothelial barrier. Two cellular pathways have been identified controlling endothelial barrier function. The normally restrictive paracellular pathway, which can become "leaky" during inflammation when gaps are induced between endothelial cells at the level of adherens and tight junctional complexes, and the transcellular pathway, which transports plasma proteins the size of albumin via transcytosis in vesicle carriers originating from cell surface caveolae. During non-inflammatory conditions, caveolae-mediated transport may be the primary mechanism of vascular permeability regulation of fluid phase molecules as well as lipids, hormones, and peptides that bind avidly to albumin. Src family protein tyrosine kinases have been implicated in the upstream signaling pathways that lead to endothelial hyperpermeability through both the paracellular and transcellular pathways. Endothelial barrier dysfunction not only affects vascular homeostasis and cell metabolism, but also governs drug delivery to underlying cells and tissues. In this review of the field, we discuss the current understanding of Src signaling in regulating paracellular and transcellular endothelial permeability pathways and effects on endogenous macromolecule and drug delivery.

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Section: Src Family Kinase Signaling In Vascular Endothelial Permeabimentioning

confidence: 99%

Regulation of endothelial permeability by Src kinase signaling: Vascular leakage versus transcellular transport of drugs and macromolecules

Place

Minshall

2008

Chemico-Biological Interactions

102

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“…Although sparse, endocytotic caveolae in the CNS endothelium provide an essential route for receptor-mediated transcytosis (19,20). This process requires Caveolin-1 (Cav-1), a transmembrane protein expressed at low levels within CNS blood vessels (21)(22)(23). Cav-1 levels are known to increase during BBB breakdown following ischemic stroke, when enhanced transcytosis initiates BBB dysfunction (24,25).…”

mentioning

confidence: 99%

Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis

Lengfeld

Lutz

Smith

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

134

127

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Disruption of the blood-brain barrier (BBB) is a defining and early feature of multiple sclerosis (MS) that directly damages the central nervous system (CNS), promotes immune cell infiltration, and influences clinical outcomes. There is an urgent need for new therapies to protect and restore BBB function, either by strengthening endothelial tight junctions or suppressing endothelial vesicular transcytosis. Although wingless integrated MMTV (Wnt)/β-catenin signaling plays an essential role in BBB formation and maintenance in healthy CNS, its role in BBB repair in neurologic diseases such as MS remains unclear. Using a Wnt/β-catenin reporter mouse and several downstream targets, we demonstrate that the Wnt/ β-catenin pathway is up-regulated in CNS endothelial cells in both human MS and the mouse model experimental autoimmune encephalomyelitis (EAE). Increased Wnt/β-catenin activity in CNS blood vessels during EAE progression correlates with up-regulation of neuronal Wnt3 expression, as well as breakdown of endothelial cell junctions. Genetic inhibition of the Wnt/β-catenin pathway in CNS endothelium before disease onset exacerbates the clinical presentation of EAE, CD4 + T-cell infiltration into the CNS, and demyelination by increasing expression of vascular cell adhesion molecule-1 and the transcytosis protein Caveolin-1 and promoting endothelial transcytosis. However, Wnt signaling attenuation does not affect the progressive degradation of tight junction proteins or paracellular BBB leakage. These results suggest that reactivation of Wnt/β-catenin signaling in CNS vessels during EAE/MS partially restores functional BBB integrity and limits immune cell infiltration into the CNS.blood-brain barrier | endothelial cell | Wnt/β-catenin signaling | MS | EAE I n both multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), leukocytes infiltrate the central nervous system (CNS) across a damaged blood-brain barrier (BBB) to mediate myelin destruction and neuronal damage (1). BBB breakdown is a contributing factor to the pathogenesis of both MS and EAE (2-4). Structural and functional BBB degradation precedes lesion development in both MS and EAE (5-9), and focal BBB abnormalities correlate with clinical exacerbations in the relapsing-remitting form of MS (10). Moreover, BBB leakage precedes the entry of T cells and monocytes into the brain parenchyma (7, 11) and coincides with early infiltration of neutrophils before the onset of EAE (12). Although the severity of barrier leakage decreases over time for most relapsing-remitting MS lesions, as assessed by gadoliniumenhancing magnetic resonance imaging (7, 13-15), whether BBB recovery is an active process and, if so, which pathways mediate its repair, remain unclear.The BBB achieves its highly selective permeability through the presence of (i) tight junctions (TJs) that prevent paracellular diffusion of small molecules and immune cells between endothelial cells (ECs), (ii) very few endocytotic vesicles that restrict movement of large mo...

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“…The results also suggested that 20 nm particles transport twofold to threefold faster than 100-120 nm particles of similar charge while positively charged particles translocated 20-to 40-fold faster than negatively charged particles. Nanoparticles can also be taken up into cells via caveolae-mediated endocytosis with eventual translocation across endothelial cells that line the lung vasculature; transcytosis mechanisms across endothelial cells are also used for nutrients or proteins (52,53) (Fig. 2).…”

Section: Translocation Of Inhaled Medication To Blood Circulationmentioning

confidence: 99%

Lung vascular targeting through inhalation delivery: Insight from filamentous viruses and other shapes

Mahmud

Discher

2011

IUBMB Life

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SummarySystemic delivery of therapeutic agents via inhalation of particulates remains an attractive, noninvasive means of administration due to the possibilities of high bioavailability and high patient compliance. Optimization of particle shapes and particle properties for deep lung deposition after inhalation continues to be one of the key challenges. Here, we review several aspects of nanoparticle design for deep lung deposition as well as the nature and extent of translocation through the air-blood barrier for local or systemic vascular targeting. We describe filamentous influenza virus in comparison to worm-like ''filomicelle'' polymers as one example of a nature inspired design. IUBMBIUBMB Life, 63(8): 607-612, 2011

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Functional and morphological studies of protein transcytosis in continuous endothelia

Cited by 92 publications

References 50 publications

Regulation of endothelial permeability by Src kinase signaling: Vascular leakage versus transcellular transport of drugs and macromolecules

Regulation of endothelial permeability by Src kinase signaling: Vascular leakage versus transcellular transport of drugs and macromolecules

Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis

Lung vascular targeting through inhalation delivery: Insight from filamentous viruses and other shapes

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