Flavanones and Chromones from Salicornia herbacea Mitigate Septic Lethality via Restoration of Vascular Barrier Integrity

2015 ◽  
Vol 63 (46) ◽  
pp. 10121-10130 ◽  
Author(s):  
Nguyen Quoc Tuan ◽  
Wonhwa Lee ◽  
Joonseok Oh ◽  
Roshan Rajan Kulkarni ◽  
Charlotte Gény ◽  
...  
Keyword(s):  
Barrier Integrity ◽  
Salicornia Herbacea ◽  
Vascular Barrier Integrity

scholarly journals Kindlin-2 interacts with endothelial adherens junctions to support vascular barrier integrity

2017 ◽  
Vol 595 (20) ◽  
pp. 6443-6462 ◽  
Author(s):  
Elzbieta Pluskota ◽  
Kamila M. Bledzka ◽  
Katarzyna Bialkowska ◽  
Dorota Szpak ◽  
Dmitry A. Soloviev ◽  
...  
Keyword(s):  
Adherens Junctions ◽  
Barrier Integrity ◽  
Vascular Barrier Integrity

Abstract 606: Antithrombin Nanoparticle Therapy Safely Restores Endothelial Barrier Integrity and Reduces Vessel Hypercoagulability in Atherosclerotic Mice

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Rohun U Palekar ◽  
Andrew P Jallouk ◽  
Hua Pan ◽  
Samuel A Wickline
Keyword(s):  
Endothelial Barrier ◽  
Thrombin Inhibitor ◽  
Saline Control ◽  
Resonance Spectroscopy ◽  
Therapeutic Effects ◽  
Thrombotic Risk ◽  
Barrier Integrity ◽  
Vascular Barrier Integrity

Introduction: Thrombin plays a major role in regulating signaling pathways responsible for atherogenesis, hypercoagulability and plaque permeability. Herein, we report the therapeutic effects of perfluorocarbon core nanoparticles (PFC-NP) conjugated to the thrombin inhibitor D-phenylalanyl-L-prolyl-L-chloromethylketone (PPACK-NP) on vascular barrier integrity and hypercoagulability. Methods and Results: ApoE-/- mice were fed a Western diet for 4 months, and received 3 doses/week of saline or 1 ml/kg PPACK-NP for the final month of feeding. Endothelial barrier integrity was assessed by quantifying the ability of atherosclerotic aortas to take up circulating semipermeable PFC-NP (~250 nm diameter). Whole aortas (arch to iliacs) were excised after 2 hour in vivo exposure to PFC-NP and underwent fluorine magnetic resonance spectroscopy ( 19 F-MRS) to quantify plaque-permeating PFC-NP. 19 F-MRS data revealed a significant decrease in plaque permeability to PFC-NP after PPACK-NP treatment compared to saline control (0.081 ± 0.011 μl PFC-NP/g aorta, N = 5 vs. 0.122 ± 0.014 μl PFC-NP/g aorta, N = 8 for PPACK-NP treated vs. saline control, p = 0.027). To assess hypercoagulability, carotid artery injury was induced photochemically to measure the time to complete occlusion as an index of thrombotic risk. Occlusion times were significantly prolonged with PPACK-NP treatment compared to untreated mice (49.8 ± 6.7 min, N = 5 vs. 26.1 ± 4.6 min, N = 9 for PPACK-NP treated vs. saline control, p = 0.019), indicating a decrease in vessel hypercoagulability after therapeutic intervention. Furthermore, PPACK-NP treatment of human aortic endothelial cells in vitro abrogated thrombin-mediated activation of surface PAR-1 receptors as measured by flow cytometry, suggesting a potential dual role for PPACK-NP in the localized modulation of both thrombosis and PAR-1 signaling. Moreover, this sustained therapeutic benefit is obtained without systemic anticoagulation as all clotting parameters and bleeding times are completely normalized within 60 minutes after i.v. injection. Conclusion: Thrombin inhibition with PPACK-NP is effective in restoring vascular barrier integrity and reducing focal thrombotic risk within a single month without incurring bleeding risk.

scholarly journals Factor VIIa binding to endothelial cell protein C receptor protects vascular barrier integrity in vivo

2014 ◽  
Vol 12 (5) ◽  
pp. 690-700 ◽  
Author(s):  
J. Sundaram ◽  
S. Keshava ◽  
R. Gopalakrishnan ◽  
C. T. Esmon ◽  
U. R. Pendurthi ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Protein C ◽  
Factor Viia ◽  
Cell Protein ◽  
Barrier Integrity ◽  
Vascular Barrier Integrity

scholarly journals Suppressing STAT3 activity protects the endothelial barrier from VEGF-mediated vascular permeability

2020 ◽  
Author(s):  
Li Wang ◽  
Matteo Astone ◽  
Sk. Kayum Alam ◽  
Zhu Zhu ◽  
Wuhong Pei ◽  
...  
Keyword(s):  
Vascular Permeability ◽  
Intercellular Adhesion Molecule ◽  
List Type ◽  
Intercellular Adhesion Molecule 1 ◽  
Potent Inducer ◽  
Barrier Integrity ◽  
Tissue Recovery ◽  
And Function ◽  
Vascular Barrier Integrity

ABSTRACTVascular permeability triggered by inflammation or ischemia promotes edema, exacerbates disease progression, and impairs tissue recovery. Vascular endothelial growth factor (VEGF) is a potent inducer of vascular permeability. VEGF plays an integral role in regulating vascular barrier function physiologically and in pathologies, such as cancer, ischemic stroke, cardiovascular disease, retinal conditions, and COVID-19-associated pulmonary edema and sepsis, which often leads to acute lung injury, including acute respiratory distress syndrome. However, after initially stimulating permeability, VEGF subsequently mediates angiogenesis to repair damaged tissue. Consequently, understanding temporal molecular regulation of VEGF-induced vascular permeability will facilitate developing therapeutics that achieve the delicate balance of inhibiting vascular permeability while preserving tissue repair. Here, we demonstrate that VEGF signals through signal transducer and activator of transcription 3 (STAT3) to promote vascular permeability. Specifically, we show that genetic STAT3 ablation reduces vascular permeability in STAT3-deficient endothelium of mice and VEGF-inducible zebrafish crossed with CRISPR/Cas9 generated genomic STAT3 knockout zebrafish. Importantly, STAT3 deficiency does not impair vascular development and function in vivo. We identify intercellular adhesion molecule 1 (ICAM-1) as a STAT3-dependent transcriptional regulator and show VEGF-dependent STAT3 activation is regulated by JAK2. Pyrimethamine, an FDA-approved anti-microbial agent that inhibits STAT3-dependent transcription, substantially reduces VEGF-induced vascular permeability in zebrafish, mouse, and human endothelium. Indeed, pharmacologically targeting STAT3 increases vascular barrier integrity using two additional compounds, atovaquone and C188-9. Collectively, our findings suggest that the VEGF, VEGFR-2, JAK2, and STAT3 signaling cascade regulates vascular barrier integrity, and inhibition of STAT3-dependent activity reduces VEGF-induced vascular permeability in vertebrate models.Key PointsGenetic STAT3 deficiency in VEGF-inducible zebrafish and mice reveals that VEGF signals through STAT3 to promote vascular permeabilityPyrimethamine, a clinically available agent that inhibits STAT3 activity, reduces VEGF-induced vascular permeability in preclinical models

scholarly journals Protection of vascular barrier integrity by activated protein C in murine models depends on protease-activated receptor-1

2009 ◽  
Vol 101 (04) ◽  
pp. 724-733 ◽  
Author(s):  
José Fernández ◽  
John Griffin ◽  
Reto Schuepbach ◽  
Clemens Feistritzer ◽  
Matthias Riewald
Keyword(s):  
Endothelial Cells ◽  
Mouse Models ◽  
Protein C ◽  
Activated Protein C ◽  
Protective Effects ◽  
Wild Type ◽  
Barrier Integrity ◽  
Protease Activated Receptor 1 ◽  
Vascular Barrier Integrity

SummaryProtease activated receptor-1 (PAR1) mediates barrier protective signalling of activated protein C (APC) in human endothelial cells in vitro and may contribute to APC’s beneficial effects in patients with severe sepsis. Mouse models are of key importance for translational research but species differences may limit conclusions for the human system. We analysed whether mouse APC can cleave, activate and induce signalling through murine PAR1 and tested in newly established mouse models if long-term infusion of APC prevents from vascular leakage. Cell surface immunoassays demonstrated efficient cleavage of endogenous murine endothelial PAR1 by either murine or human APC. Pharmacological concentrations of APC of either species had powerful barrier protective effects on cultured murine endothelial cells that required PAR1 cleavage. Vascular endothelial growth factor-mediated hyperpermeability in the skin was reduced by either endogenously generated as well as directly infused recombinant mouse APC in wild-type mice. However APC did not significantly alter the vascular barrier function in PAR1-deficient mice. In endotoxin-challenged mice, infused APC significantly prevented from pulmonary fluid accumulation in the wild-type mice but not in mice lacking PAR1. Our results directly show that murine APC cleaves and signals through PAR1 in mouse endothelial cells. APC reduces vascular permeability in mouse models and PAR1 plays a major role in mediating these effects. Our data in vitro and in vivo support the paradigm that PAR1 contributes to protective effects of APC on vascular barrier integrity in sepsis.

scholarly journals Quantifying the effects of engineered nanomaterials on endothelial cell architecture and vascular barrier integrity using a cell pair model

Nanoscale ◽  
2019 ◽  
Vol 11 (38) ◽  
pp. 17878-17893 ◽  
Author(s):  
Feyisayo Eweje ◽  
Herdeline Ann M. Ardoña ◽  
John F. Zimmerman ◽  
Blakely B. O'Connor ◽  
Seungkuk Ahn ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cellular Level ◽  
Engineered Nanomaterials ◽  
Barrier Integrity ◽  
Cell Pair ◽  
Pair Model ◽  
Cell Architecture ◽  
A Cell ◽  
The Impact ◽  
Vascular Barrier Integrity

Micropatterned endothelial cell pairs enable the analysis of the impact of nanomaterial exposure on cellular-level remodeling processes and vascular barrier integrity.

scholarly journals P53 in lung vascular barrier dysfunction

2020 ◽  
Vol 2 (1) ◽  
pp. E1-E2 ◽  
Author(s):  
Nektarios Barabutis
Keyword(s):  
Distress Syndrome ◽  
Heat Shock Protein 90 ◽  
Tumor Suppressor Protein ◽  
Molecular Pathways ◽  
Barrier Dysfunction ◽  
Barrier Integrity ◽  
Beneficial Effects ◽  
Endothelial Barrier Dysfunction ◽  
Hormone Antagonists ◽  
Vascular Barrier Integrity

Endothelial barrier dysfunction is the hallmark of inflammatory lung disease, including Acute Lung Injury and Acute Respiratory Distress Syndrome. The purpose of the present editorial is to emphasize on recent advances in the corresponding field, as it relates to P53. This tumor suppressor protein has been shown to enhance the vascular barrier integrity via distinct molecular pathways. Further, it mediates the beneficial effects of heat shock protein 90 inhibitors and growth hormone releasing hormone antagonists in the lung microvasculature.

scholarly journals TAK1 Signaling Downstream of PAR‐1 in Endothelial Cells Restores Lung Vascular Barrier Integrity

2015 ◽  
Vol 29 (S1) ◽  
Author(s):  
Dheeraj Soni ◽  
Auditi DebRoy ◽  
DongMei Wang ◽  
Stephen Vogel ◽  
Chinnaswamy Tiruppathi
Keyword(s):  
Endothelial Cells ◽  
Barrier Integrity ◽  
Vascular Barrier Integrity
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