scholarly journals Endothelial Semaphorin 3F Maintains Endothelial Barrier Function and Inhibits Monocyte Migration

2020 ◽  
Vol 21 (4) ◽  
pp. 1471 ◽  
Author(s):  
Huayu Zhang ◽  
Dianne Vreeken ◽  
Abidemi Junaid ◽  
Gangqi Wang ◽  
Wendy M. P. J. Sol ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Laminar Flow ◽  
Barrier Function ◽  
Vascular Inflammation ◽  
Microfluidic System ◽  
Class Iii ◽  
Monocyte Migration ◽  
Inflammatory Conditions ◽  
Semaphorin 3F ◽  
Heparan Sulfates

In normal physiology, endothelial cells (ECs) form a vital barrier between the blood and underlying tissue controlling leukocyte diapedesis and vascular inflammation. Emerging data suggest that neuronal guidance cues, typically expressed during development, have roles outside the nervous system in vascular biology and immune responses. In particular, Class III semaphorins have been reported to affect EC migration and angiogenesis. While ECs express high levels of semaphorin 3F (SEMA3F), little is known about its function in mature ECs. Here we show that SEMA3F expression is reduced by inflammatory stimuli and increased by laminar flow. Endothelial cells exposed to laminar flow secrete SEMA3F, which subsequently binds to heparan sulfates on the surface of ECs. However, under pro-inflammatory conditions, reduced levels of SEMA3F make ECs more prone to monocyte diapedesis and display impaired barrier function as measured with an electric cell–substrate impedance sensing system and a microfluidic system. In addition, we demonstrate that SEMA3F can directly inhibit the migration of activated monocytes. Taken together, our data suggest an important homeostatic function for EC-expressed SEMA3F, serving as a mediator of endothelial quiescence.

The neuronal guidance cue semaphorin 3F is highly expressed by endothelial cells upon laminar flow and inhibit monocyte migration

2016 ◽  
Vol 252 ◽  
pp. e157
Author(s):  
H. Zhang ◽  
R.G. de Bruin ◽  
W.M.P.J. Sol ◽  
E.P. van der Veer ◽  
B.M. van den Berg ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Laminar Flow ◽  
Monocyte Migration ◽  
Guidance Cue ◽  
Semaphorin 3F ◽  
Neuronal Guidance

scholarly journals Podocalyxin is required for maintaining blood–brain barrier function during acute inflammation

2019 ◽  
Vol 116 (10) ◽  
pp. 4518-4527 ◽  
Author(s):  
Jessica Cait ◽  
Michael R. Hughes ◽  
Matthew R. Zeglinski ◽  
Allen W. Chan ◽  
Sabrina Osterhof ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Barrier Function ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
Focal Adhesions ◽  
Brain Barrier ◽  
Cortical Actin ◽  
Inflammatory Conditions ◽  
Blood Brain

Podocalyxin (Podxl) is broadly expressed on the luminal face of most blood vessels in adult vertebrates, yet its function on these cells is poorly defined. In the present study, we identified specific functions for Podxl in maintaining endothelial barrier function. Using electrical cell substrate impedance sensing and live imaging, we found that, in the absence of Podxl, human umbilical vein endothelial cells fail to form an efficient barrier when plated on several extracellular matrix substrates. In addition, these monolayers lack adherens junctions and focal adhesions and display a disorganized cortical actin cytoskeleton. Thus, Podxl has a key role in promoting the appropriate endothelial morphogenesis required to form functional barriers. This conclusion is further supported by analyses of mutant mice in which we conditionally deleted a floxed allele ofPodxlin vascular endothelial cells (vECs) using Tie2Cre mice (PodxlΔTie2Cre). Although we did not detect substantially altered permeability in naïve mice, systemic priming with lipopolysaccharide (LPS) selectively disrupted the blood–brain barrier (BBB) inPodxlΔTie2Cremice. To study the potential consequence of this BBB breach, we used a selective agonist (TFLLR-NH2) of the protease-activated receptor-1 (PAR-1), a thrombin receptor expressed by vECs, neuronal cells, and glial cells. In response to systemic administration of TFLLR-NH2, LPS-primedPodxlΔTie2Cremice become completely immobilized for a 5-min period, coinciding with severely dampened neuroelectric activity. We conclude that Podxl expression by CNS tissue vECs is essential for BBB maintenance under inflammatory conditions.

Regulation of coronary venular barrier function by blood borne inflammatory mediators and pharmacological tools: insights from novel microvascular wall models

2012 ◽  
Vol 302 (3) ◽  
pp. H567-H581 ◽  
Author(s):  
Gerd Juchem ◽  
Dominik R. Weiss ◽  
Maria Knott ◽  
Anton Senftl ◽  
Stefan Förch ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Inflammatory Mediators ◽  
Barrier Function ◽  
Platelet Activating Factor ◽  
Fold Increase ◽  
Human Myocardium ◽  
Polymorphonuclear Leucocytes ◽  
Inflammatory Conditions ◽  
Vascular Walls

We hypothesized that postcapillary venules play a central role in the control of the tightness of the coronary system as a whole, particularly under inflammatory conditions. Sandwich cultures of endothelial cells and pericytes of precapillary arteriolar or postcapillary venular origin from human myocardium as models of the respective vascular walls (sandwich cultures of precapillary arteriolar or postcapillary venular origin) were exposed to thrombin and components of the acutely activatable inflammatory system, and their hydraulic conductivity ( LP) was registered. LP of SC-PAO remained low under all conditions (3.24 ± 0.52·10−8cm·s−1·cmH2O−1). In contrast, in the venular wall model, PGE2, platelet-activating factor (PAF), leukotriene B4 (LTB4), IL-6, and IL-8 induced a prompt, concentration-dependent, up to 10-fold increase in LP with synergistic support when combined. PAF and LTB4 released by metabolically cooperating platelets, and polymorphonuclear leucocytes (PMNs) caused selectively venular endothelial cells to contract and to open their clefts widely. This breakdown of the barrier function was preventable and even reversible within 6–8 h by the presence of 50 μM quercetin glucuronide (QG). LTB4 synthesis was facilitated by biochemical involvement of erythrocytes. Platelets segregated in the arterioles and PMNs in the venules of blood-perfused human myocardium (histological studies on donor hearts refused for heart transplantation). Extrapolating these findings to the coronary microcirculation in vivo would imply that the latter's complex functionality after accumulation of blood borne inflammatory mediators can change rapidly due to selective breakdown of the postcapillary venular barrier. The resulting inflammatory edema and venulo-thrombosis will severely impair myocardial performance. The protection afforded by QG could be of particular relevance in the context of cardiosurgical intervention.

scholarly journals Downregulation of Endothelial Plexin A4 Under Inflammatory Conditions Impairs Vascular Integrity

2021 ◽  
Vol 8 ◽  
Author(s):  
Dianne Vreeken ◽  
Caroline Suzanne Bruikman ◽  
Wendy Stam ◽  
Stefan Martinus Leonardus Cox ◽  
Zsófia Nagy ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Barrier Function ◽  
Network Formation ◽  
Cell Types ◽  
Vascular Leakage ◽  
Cell Junctions ◽  
Mrna Levels ◽  
Human Monocytes ◽  
Vascular Integrity ◽  
Inflammatory Conditions

Objective: Besides hyperlipidemia, inflammation is an important determinant in the initiation and the progression of atherosclerosis. As Neuroimmune Guidance Cues (NGCs) are emerging as regulators of atherosclerosis, we set out to investigate the expression and function of inflammation-regulated NGCs.Methods and results: NGC expression in human monocytes and endothelial cells was assessed using a publicly available RNA dataset. Next, the mRNA levels of expressed NGCs were analyzed in primary human monocytes and endothelial cells after stimulation with IL1β or TNFα. Upon stimulation a total of 14 and 19 NGCs in monocytes and endothelial cells, respectively, were differentially expressed. Since plexin A4 (PLXNA4) was strongly downregulated in endothelial cells under inflammatory conditions, the role of PLXNA4 in endothelial function was investigated. Knockdown of PLXNA4 in endothelial cells markedly impaired the integrity of the monolayer leading to more elongated cells with an inflammatory phenotype. In addition, these cells showed an increase in actin stress fibers and decreased cell-cell junctions. Functional assays revealed decreased barrier function and capillary network formation of the endothelial cells, while vascular leakage and trans-endothelial migration of monocytes was increased.Conclusion: The current study demonstrates that pro-inflammatory conditions result in differential expression of NGCs in endothelial cells and monocytes, both culprit cell types in atherosclerosis. Specifically, endothelial PLXNA4 is reduced upon inflammation, while PLXNA4 maintains endothelial barrier function thereby preventing vascular leakage of fluids as well as cells. Taken together, PLXNA4 may well have a causal role in atherogenesis that deserves further investigation.

scholarly journals Vascular Inflammation Is Associated with Loss of Aquaporin 1 Expression on Endothelial Cells and Increased Fluid Leakage in SARS-CoV-2 Infected Golden Syrian Hamsters

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 639
Author(s):  
Lisa Allnoch ◽  
Georg Beythien ◽  
Eva Leitzen ◽  
Kathrin Becker ◽  
Franz-Josef Kaup ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Inflammation ◽  
Intercellular Junctions ◽  
Edema Formation ◽  
Vascular Integrity ◽  
Syrian Hamsters ◽  
Aquaporin 1 ◽  
Vascular Walls ◽  
Transmission Electron ◽  
Mock Infection

Vascular changes represent a characteristic feature of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection leading to a breakdown of the vascular barrier and subsequent edema formation. The aim of this study was to provide a detailed characterization of the vascular alterations during SARS-CoV-2 infection and to evaluate the impaired vascular integrity. Groups of ten golden Syrian hamsters were infected intranasally with SARS-CoV-2 or phosphate-buffered saline (mock infection). Necropsies were performed at 1, 3, 6, and 14 days post-infection (dpi). Lung samples were investigated using hematoxylin and eosin, alcian blue, immunohistochemistry targeting aquaporin 1, CD3, CD204, CD31, laminin, myeloperoxidase, SARS-CoV-2 nucleoprotein, and transmission electron microscopy. SARS-CoV-2 infected animals showed endothelial hypertrophy, endothelialitis, and vasculitis. Inflammation mainly consisted of macrophages and lower numbers of T-lymphocytes and neutrophils/heterophils infiltrating the vascular walls as well as the perivascular region at 3 and 6 dpi. Affected vessels showed edema formation in association with loss of aquaporin 1 on endothelial cells. In addition, an ultrastructural investigation revealed disruption of the endothelium. Summarized, the presented findings indicate that loss of aquaporin 1 entails the loss of intercellular junctions resulting in paracellular leakage of edema as a key pathogenic mechanism in SARS-CoV-2 triggered pulmonary lesions.

scholarly journals Poldip2 controls leukocyte infiltration into the ischemic brain by regulating focal adhesion kinase-mediated VCAM-1 induction

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lori N. Eidson ◽  
Qingzeng Gao ◽  
Hongyan Qu ◽  
Daniel S. Kikuchi ◽  
Ana Carolina P. Campos ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cerebral Ischemia ◽  
Focal Adhesion Kinase ◽  
Adhesion Molecules ◽  
Focal Adhesion ◽  
Vascular Inflammation ◽  
Leukocyte Recruitment ◽  
Ischemic Brain ◽  
Inflammatory Monocytes

AbstractStroke is a multiphasic process involving a direct ischemic brain injury which is then exacerbated by the influx of immune cells into the brain tissue. Activation of brain endothelial cells leads to the expression of adhesion molecules such vascular cell adhesion molecule 1 (VCAM-1) on endothelial cells, further increasing leukocyte recruitment. Polymerase δ-interacting protein 2 (Poldip2) promotes brain vascular inflammation and leukocyte recruitment via unknown mechanisms. This study aimed to define the role of Poldip2 in mediating vascular inflammation and leukocyte recruitment following cerebral ischemia. Cerebral ischemia was induced in Poldip2+/+ and Poldip2+/− mice and brains were isolated and processed for flow cytometry or RT-PCR. Cultured rat brain microvascular endothelial cells were used to investigate the effect of Poldip2 depletion on focal adhesion kinase (FAK)-mediated VCAM-1 induction. Poldip2 depletion in vivo attenuated the infiltration of myeloid cells, inflammatory monocytes/macrophages and decreased the induction of adhesion molecules. Focusing on VCAM-1, we demonstrated mechanistically that FAK activation was a critical intermediary in Poldip2-mediated VCAM-1 induction. In conclusion, Poldip2 is an important mediator of endothelial dysfunction and leukocyte recruitment. Thus, Poldip2 could be a therapeutic target to improve morbidity following ischemic stroke.

scholarly journals Screening for Interacting Proteins with Peptide Biomarker of Blood–Brain Barrier Alteration under Inflammatory Conditions

2021 ◽  
Vol 22 (9) ◽  
pp. 4725
Author(s):  
Karina Vargas-Sanchez ◽  
Monica Losada-Barragán ◽  
Maria Mogilevskaya ◽  
Susana Novoa-Herrán ◽  
Yehidi Medina ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Neurovascular Unit ◽  
Specific Interaction ◽  
Brain Barrier ◽  
Mass Spectrometry Analysis ◽  
Peptide Ligand ◽  
Inflammatory Conditions ◽  
Blood Brain ◽  
Potential Biomarker

Neurodegenerative diseases are characterized by increased permeability of the blood–brain barrier (BBB) due to alterations in cellular and structural components of the neurovascular unit, particularly in association with neuroinflammation. A previous screening study of peptide ligands to identify molecular alterations of the BBB in neuroinflammation by phage-display, revealed that phage clone 88 presented specific binding affinity to endothelial cells under inflammatory conditions in vivo and in vitro. Here, we aimed to identify the possible target receptor of the peptide ligand 88 expressed under inflammatory conditions. A cross-link test between phage-peptide-88 with IL-1β-stimulated human hCMEC cells, followed by mass spectrometry analysis, was used to identify the target of peptide-88. We modeled the epitope–receptor molecular interaction between peptide-88 and its target by using docking simulations. Three proteins were selected as potential target candidates and tested in enzyme-linked immunosorbent assays with peptide-88: fibronectin, laminin subunit α5 and laminin subunit β-1. Among them, only laminin subunit β-1 presented measurable interaction with peptide-88. Peptide-88 showed specific interaction with laminin subunit β-1, highlighting its importance as a potential biomarker of the laminin changes that may occur at the BBB endothelial cells under pathological inflammation conditions.

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