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

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 Investigating VCAM-1 Targeted Nanoparticles and Annexin A1 Therapy using Dysfunctional-endothelium-on-a-chip

2021 ◽  
Author(s):  
Salime Bazban-Shotorbani ◽  
Nazila Kamaly
Keyword(s):  
Cell Adhesion Molecule ◽  
Adherens Junctions ◽  
Main Role ◽  
Annexin A1 ◽  
Pathological Stage ◽  
Vascular Cell Adhesion ◽  
Barrier Integrity ◽  
Targeted Nanoparticles ◽  
Treatment Regimens ◽  
Cell Adhesion Molecule 1

Atherosclerosis is an inflammation-driven disease of the arteries and one of the leading causes of global mortality. The initial pathological stage in atherosclerosis is dysfunctional endothelium (Dys-En), which results in loss of adherens-junctions between cells, thus enhancing permeability. Not only the enhanced permeability of Dys-En can be used as a nanoparticle targeting mechanism, but also the normalization and restoration of this phenomenon can be utilized as a potent anti-atherosclerotic therapy. This study aimed to recruit a robust biomicrofluidic model of Dys-En for 1) nanoparticle screening and 2) normalization assessments. The developed Dys-En-on-a-chip could successfully mimic the atherosclerotic flow condition, enhanced permeability, formation of actin stress fibers, and overexpression of vascular cell adhesion molecule 1 (VCAM-1), which are known as hallmarks of a Dys-En. The screening of VCAM-1 targeting nanoparticles with variable biophysicochemical properties showed that nanoparticle size plays the main role in nanoparticle targeting, and the design of nanoparticles in the range of 30-60 nm can highly increase their targeting to Dys-En. Moreover, treatment of Dys-En-on-a-chip with Annexin A1, as a novel pro-resolving mediator, resulted in restoration of adherens-junctions and normalization of the barrier integrity. This data validates the use of biomicrofluidic models for investigating treatment regimens with biologics and to identify optimal nanoparticle properties for effective atherosclerotic plaque targeting.

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 Brain barriers: Crosstalk between complex tight junctions and adherens junctions

2015 ◽  
Vol 209 (4) ◽  
pp. 493-506 ◽  
Author(s):  
Silvia Tietz ◽  
Britta Engelhardt
Keyword(s):  
Tight Junctions ◽  
Adherens Junctions ◽  
Brain Barrier ◽  
Microvascular Endothelial Cells ◽  
Barrier Integrity ◽  
Promising Target ◽  
The Central Nervous System ◽  
Junctional Complexes ◽  
Paracellular Diffusion ◽  
Brain Barriers

Unique intercellular junctional complexes between the central nervous system (CNS) microvascular endothelial cells and the choroid plexus epithelial cells form the endothelial blood–brain barrier (BBB) and the epithelial blood–cerebrospinal fluid barrier (BCSFB), respectively. These barriers inhibit paracellular diffusion, thereby protecting the CNS from fluctuations in the blood. Studies of brain barrier integrity during development, normal physiology, and disease have focused on BBB and BCSFB tight junctions but not the corresponding endothelial and epithelial adherens junctions. The crosstalk between adherens junctions and tight junctions in maintaining barrier integrity is an understudied area that may represent a promising target for influencing brain barrier function.

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.

Sign in / Sign up

Export Citation Format

Share Document