Endothelial Hyaluronan Synthase 3 Augments Postischemic Arteriogenesis Through CD44/eNOS Signaling

2021 ◽  
Author(s):  
Rebekka Schneckmann ◽  
Tatsiana Suvorava ◽  
Christian Hundhausen ◽  
Dominik Schuler ◽  
Christin Lorenz ◽  
...  
Keyword(s):  
Cell Function ◽  
Immune Cell ◽  
Blood Perfusion ◽  
Endothelial Glycocalyx ◽  
Hyaluronan Synthase ◽  
Flow Mediated Dilation ◽  
Hindlimb Ischemia ◽  
Endothelial Cell Function ◽  
Cell Functions

Objective: The dominant driver of arteriogenesis is elevated shear stress sensed by the endothelial glycocalyx thereby promoting arterial outward remodeling. Hyaluronan, a critical component of the endothelial glycocalyx, is synthesized by 3 different HAS1, -2, and -3 (hyaluronan synthase isoenzymes) at the plasma membrane. Considering further the importance of HAS3 for smooth muscle cell and immune cell functions we aimed to evaluate its role in collateral artery growth. Approach and Results: Male Has3 -deficient ( Has3 -KO) mice were subjected to hindlimb ischemia. Blood perfusion was monitored by laser Doppler perfusion imaging and endothelial function was assessed by measurement of flow-mediated dilation in vivo. Collateral remodeling was monitored by high resolution magnetic resonance angiography. A neutralizing antibody against CD44 (clone KM201) was injected intraperitoneally to analyze hyaluronan signaling in vivo. After hindlimb ischemia, Has3 -KO mice showed a reduced arteriogenic response with decreased collateral remodeling and impaired perfusion recovery. While postischemic leukocyte infiltration was unaffected, a diminished flow-mediated dilation pointed towards an impaired endothelial cell function. Indeed, endothelial AKT-dependent eNOS (endothelial nitric oxide synthase) phosphorylation at Ser1177 was substantially reduced in Has3 -KO thigh muscles. Endothelial-specific Has3 -KO mice mimicked the hindlimb ischemia-induced phenotype of impaired perfusion recovery as observed in global Has3 -deficiency. Mechanistically, blocking selectively the hyaluronan binding site of CD44 reduced flow-mediated dilation, thereby suggesting hyaluronan signaling through CD44 as the underlying signaling pathway. Conclusions: In summary, HAS3 contributes to arteriogenesis in hindlimb ischemia by hyaluronan/CD44-mediated stimulation of eNOS phosphorylation at Ser1177. Thus, strategies augmenting endothelial HAS3 or CD44 could be envisioned to enhance vascularization under pathological conditions.

scholarly journals Ets1 and Ets2 are required for endothelial cell survival during embryonic angiogenesis

Blood ◽  
2009 ◽  
Vol 114 (5) ◽  
pp. 1123-1130 ◽  
Author(s):  
Guo Wei ◽  
Ruchika Srinivasan ◽  
Carmen Z. Cantemir-Stone ◽  
Sudarshana M. Sharma ◽  
Ramasamy Santhanam ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Target Genes ◽  
Cell Function ◽  
Endothelial Cell Function ◽  
Cell Functions ◽  
And Function ◽  
Target Promoters ◽  
Vascular Branching

Abstract The ras/Raf/Mek/Erk pathway plays a central role in coordinating endothelial cell activities during angiogenesis. Transcription factors Ets1 and Ets2 are targets of ras/Erk signaling pathways that have been implicated in endothelial cell function in vitro, but their precise role in vascular formation and function in vivo remains ill-defined. In this work, mutation of both Ets1 and Ets2 resulted in embryonic lethality at midgestation, with striking defects in vascular branching having been observed. The action of these factors was endothelial cell autonomous as demonstrated using Cre/loxP technology. Analysis of Ets1/Ets2 target genes in isolated embryonic endothelial cells demonstrated down-regulation of Mmp9, Bcl-XL, and cIAP2 in double mutants versus controls, and chromatin immunoprecipitation revealed that both Ets1 and Ets2 were loaded at target promoters. Consistent with these observations, endothelial cell apoptosis was significantly increased both in vivo and in vitro when both Ets1 and Ets2 were mutated. These results establish essential and overlapping functions for Ets1 and Ets2 in coordinating endothelial cell functions with survival during embryonic angiogenesis.

scholarly journals Erratum: Bisphosphonate-induced differential modulation of immune cell function in gingiva and bone marrow in vivo: Role in osteoclast-mediated NK cell activation

Oncotarget ◽  
2015 ◽  
Vol 6 (38) ◽  
pp. 41398-41398 ◽  
Author(s):  
Han-Ching Tseng ◽  
Keiichi Kanayama ◽  
Kawaljit Kaur ◽  
So-Hyun Park ◽  
Sil Park ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Nk Cell ◽  
Differential Modulation ◽  
Immune Cell Function

scholarly journals Resolvins as Regulators of the Immune System

2010 ◽  
Vol 10 ◽  
pp. 818-831 ◽  
Author(s):  
Hiroyuki Seki ◽  
Takaharu Sasaki ◽  
Tomomi Ueda ◽  
Makoto Arita
Keyword(s):  
Immune System ◽  
Acute Inflammation ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Bioactive Metabolites ◽  
Cell Functions ◽  
First Response ◽  
Beneficial Impact

Inflammation is the first response of the immune system to infection or injury, but excessive or inappropriate inflammatory responses contribute to a range of acute and chronic human diseases. Clinical assessment of dietary supplementation of ω-3 polyunsaturated fatty acids (i.e., eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) indicate that they have beneficial impact on these diseases, although the mechanisms are poorly understood at the molecular level. In this decade, it has been revealed that EPA and DHA are enzymatically converted to bioactive metabolites in the course of acute inflammation and resolution. These metabolites were shown to regulate immune cell functions and to display potent anti-inflammatory actions bothin vitroandin vivo. Because of their ability to resolve an acute inflammatory response, they are referred to as proresolving mediators, or resolvins. In this review, we provide an overview of the formation and actions of these lipid mediators.

scholarly journals Administration of cardiac mesenchymal cells modulates innate immunity in the acute phase of myocardial infarction in mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yi Kang ◽  
Marjan Nasr ◽  
Yiru Guo ◽  
Shizuka Uchida ◽  
Tyler Weirick ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Innate Immunity ◽  
Mechanism Of Action ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Mesenchymal Cell ◽  
Cell Types

Abstract Although cardiac mesenchymal cell (CMC) therapy mitigates post-infarct cardiac dysfunction, the underlying mechanisms remain unidentified. It is acknowledged that donor cells are neither appreciably retained nor meaningfully contribute to tissue regeneration—suggesting a paracrine-mediated mechanism of action. As the immune system is inextricably linked to wound healing/remodeling in the ischemically injured heart, the reparative actions of CMCs may be attributed to their immunoregulatory properties. The current study evaluated the consequences of CMC administration on post myocardial infarction (MI) immune responses in vivo and paracrine-mediated immune cell function in vitro. CMC administration preferentially elicited the recruitment of cell types associated with innate immunity (e.g., monocytes/macrophages and neutrophils). CMC paracrine signaling assays revealed enhancement in innate immune cell chemoattraction, survival, and phagocytosis, and diminished pro-inflammatory immune cell activation; data that identifies and catalogues fundamental immunomodulatory properties of CMCs, which have broad implications regarding the mechanism of action of CMCs in cardiac repair.

scholarly journals Critical Analysis of Non-Thermal Plasma-Driven Modulation of Immune Cells from Clinical Perspective

2020 ◽  
Vol 21 (17) ◽  
pp. 6226 ◽  
Author(s):  
Barbora Smolková ◽  
Adam Frtús ◽  
Mariia Uzhytchak ◽  
Mariia Lunova ◽  
Šárka Kubinová ◽  
...  
Keyword(s):  
Immune Cells ◽  
Thermal Plasma ◽  
Critical Analysis ◽  
Cell Function ◽  
Immune Cell ◽  
Real Life ◽  
Research Strategy ◽  
Cellular Mechanisms ◽  
Non Thermal Plasma

The emerged field of non-thermal plasma (NTP) shows great potential in the alteration of cell redox status, which can be utilized as a promising therapeutic implication. In recent years, the NTP field considerably progresses in the modulation of immune cell function leading to promising in vivo results. In fact, understanding the underlying cellular mechanisms triggered by NTP remains incomplete. In order to boost the field closer to real-life clinical applications, there is a need for a critical overview of the current state-of-the-art. In this review, we conduct a critical analysis of the NTP-triggered modulation of immune cells. Importantly, we analyze pitfalls in the field and identify persisting challenges. We show that the identification of misconceptions opens a door to the development of a research strategy to overcome these limitations. Finally, we propose the idea that solving problems highlighted in this review will accelerate the clinical translation of NTP-based treatments.

Human proximal tubular epithelial cells express somatostatin: regulation by growth factors and cAMP

1998 ◽  
Vol 274 (6) ◽  
pp. F1095-F1101 ◽  
Author(s):  
Martin A. Turman ◽  
Courtney A. Apple
Keyword(s):  
Epithelial Cells ◽  
Cell Function ◽  
Tubular Cell ◽  
Human Thyroid ◽  
Renal Tubular Cell ◽  
Tubular Epithelial Cells ◽  
Cell Functions ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular

Somatostatin modulates several renal tubular cell functions, including gluconeogenesis and proliferation. In this study, we demonstrate that cultured human proximal tubular epithelial cells (PTEC) express somatostatin. We also demonstrate positive and negative regulation of PTEC somatostatin production. We found that PTEC derived from 14 different human donors consistently expressed somatostatin mRNA and/or peptide as detected by RT-PCR and enzyme-linked immunoassay. Furthermore, Northern blot analysis revealed that PTEC express the same size mRNA transcript (750 nucleotides) as human thyroid carcinoma (TT) cells. The PTEC mitogens, epidermal growth factor (EGF) and hydrocortisone, inhibit PTEC somatostatin secretion, whereas forskolin (a direct stimulator of adenylate cyclase) and fetal bovine serum stimulate secretion. These findings raise the possibility that renal-derived somatostatin modulates tubular cell function in an autocrine/paracrine manner. Manipulation of this pathway may lead to novel methods with which to alter tubular cell proliferation and function in vivo.

scholarly journals Targeting QKI-7 in vivo restores endothelial cell function in diabetes

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Chunbo Yang ◽  
Magdalini Eleftheriadou ◽  
Sophia Kelaini ◽  
Thomas Morrison ◽  
Marta Vilà González ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Function ◽  
Vascular Endothelial Cell ◽  
Vascular Complications ◽  
Limb Ischemia ◽  
Limb Amputation ◽  
Diabetic Patients ◽  
Ips Cell ◽  
Endothelial Cell Function

Abstract Vascular endothelial cell (EC) dysfunction plays a key role in diabetic complications. This study discovers significant upregulation of Quaking-7 (QKI-7) in iPS cell-derived ECs when exposed to hyperglycemia, and in human iPS-ECs from diabetic patients. QKI-7 is also highly expressed in human coronary arterial ECs from diabetic donors, and on blood vessels from diabetic critical limb ischemia patients undergoing a lower-limb amputation. QKI-7 expression is tightly controlled by RNA splicing factors CUG-BP and hnRNPM through direct binding. QKI-7 upregulation is correlated with disrupted cell barrier, compromised angiogenesis and enhanced monocyte adhesion. RNA immunoprecipitation (RIP) and mRNA-decay assays reveal that QKI-7 binds and promotes mRNA degradation of downstream targets CD144, Neuroligin 1 (NLGN1), and TNF-α-stimulated gene/protein 6 (TSG-6). When hindlimb ischemia is induced in diabetic mice and QKI-7 is knocked-down in vivo in ECs, reperfusion and blood flow recovery are markedly promoted. Manipulation of QKI-7 represents a promising strategy for the treatment of diabetic vascular complications.

scholarly journals IMMU-46. EXAMINATION OF THE EFFECTS OF DEXAMETHASONE ON THE EFFICACY OF IMMUNOTHERAPY IN GLIOMA USING GENE-MEDIATED CYTOTOXIC IMMUNOTHERAPY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi129-vi129
Author(s):  
Marilin Koch ◽  
Mykola Zdioruk ◽  
M Oskar Nowicki ◽  
Estuardo Aguilar ◽  
Laura Aguilar ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Symptomatic Treatment ◽  
Tumor Cell Death ◽  
The Impact

Abstract RATIONALE Dexamethasone is frequently used in symptomatic treatment of glioma patients, although it is known to cause immune suppression. Checkpoint inhibitor immunotherapies have not yet been successful in glioma treatments. Gene-mediated cytotoxic immunotherapy (GMCI) is an immunotherapeutic approach that uses aglatimagene besadenovec with an anti-herpetic prodrug to induce immunogenic tumor cell death and immune cell attraction to the tumor site with potent CD8 T cell activation. GMCI is currently in clinical trials for solid tumors including glioblastoma, where it showed encouraging survival results in a Phase 2 study that did not limit the use of dexamethasone. However, the effects of dexamethasone on its efficacy have not been explored. METHODS We investigated the effects of dexamethasone on GMCI in vitro using cytotoxicity and T-cell-killing assays in glioblastoma cell lines. The impact of dexamethasone in vivo was assessed in an orthotopic syngeneic murine glioblastoma model. RESULTS Cyotoxicity assays showed that Dexamethasone has a slight impact on GMCI in vitro. In contrast, we observed a highly significant effect in T-cell-functional assays in which killing was greatly impaired. Immune cell response assays revealed a reduced T-cell proliferation after co-culture with supernatant from dexamethasone or combination treated glioblastoma cells in contrast to GMCI alone. In a murine model, the combination of GMCI and dexamethasone resulted in a significant reduction in median symptom-free survival (29d) in comparison to GMCI alone (39.5d) (P = 0.0184). CONCLUSION Our data suggest that high doses of dexamethasone may negatively impact the efficacy of immunotherapy for glioma, which may be a consequence of impaired T cell function. These results support the idea that there is a need in identifying possible alternatives to dexamethasone to maximize the effectiveness of immunostimulatory therapies such as GMCI.

scholarly journals Glucose Triggers ATP Secretion from Bacteria in a Growth-Phase-Dependent Manner

2013 ◽  
Vol 79 (7) ◽  
pp. 2328-2335 ◽  
Author(s):  
Ippei Hironaka ◽  
Tadayuki Iwase ◽  
Shinya Sugimoto ◽  
Ken-ichi Okuda ◽  
Akiko Tajima ◽  
...  
Keyword(s):  
Stationary Phase ◽  
Growth Phase ◽  
Cell Function ◽  
Immune Cell ◽  
Dependent Manner ◽  
T Helper 17 ◽  
Content Type ◽  
Cell Functions ◽  
Atp Secretion ◽  
Enterococcus Gallinarum

ABSTRACTATP modulates immune cell functions, and ATP derived from gut commensal bacteria promotes the differentiation of T helper 17 (Th17) cells in the intestinal lamina propria. We recently reported thatEnterococcus gallinarum, isolated from mice and humans, secretes ATP. We have since found and characterized several ATP-secreting bacteria. Of the tested enterococci,Enterococcus mundtiisecreted the greatest amount of ATP (>2 μM/108cells) after overnight culture. Glucose, not amino acids and vitamins, was essential for ATP secretion fromE. mundtii. Analyses of energy-deprived cells demonstrated that glycolysis is the most important pathway for bacterial ATP secretion. Furthermore, exponential-phaseE. mundtiiandEnterococcus faecaliscells secrete ATP more efficiently than stationary-phase cells. Other bacteria, includingPseudomonas aeruginosa,Escherichia coli, andStaphylococcus aureus, also secrete ATP in exponential but not stationary phase. These results suggest that various gut bacteria, including commensals and pathogens, might secrete ATP at any growth phase and modulate immune cell function.

scholarly journals The small GTPase Rap1b negatively regulates neutrophil chemotaxis and transcellular diapedesis by inhibiting Akt activation

2014 ◽  
Vol 211 (9) ◽  
pp. 1741-1758 ◽  
Author(s):  
Sachin Kumar ◽  
Juying Xu ◽  
Rupali Sani Kumar ◽  
Sribalaji Lakshmikanthan ◽  
Reuben Kapur ◽  
...  
Keyword(s):  
Immune Cell ◽  
Neutrophil Migration ◽  
Clinical Importance ◽  
Endotoxin Shock ◽  
Small Gtpase ◽  
Akt Activation ◽  
Cellular Defense ◽  
Cell Functions

Neutrophils are the first line of cellular defense in response to infections and inflammatory injuries. However, neutrophil activation and accumulation into tissues trigger tissue damage due to release of a plethora of toxic oxidants and proteases, a cause of acute lung injury (ALI). Despite its clinical importance, the molecular regulation of neutrophil migration is poorly understood. The small GTPase Rap1b is generally viewed as a positive regulator of immune cell functions by controlling bidirectional integrin signaling. However, we found that Rap1b-deficient mice exhibited enhanced neutrophil recruitment to inflamed lungs and enhanced susceptibility to endotoxin shock. Unexpectedly, Rap1b deficiency promoted the transcellular route of diapedesis through endothelial cell. Increased transcellular migration of Rap1b-deficient neutrophils in vitro was selectively mediated by enhanced PI3K-Akt activation and invadopodia-like protrusions. Akt inhibition in vivo suppressed excessive Rap1b-deficient neutrophil migration and associated endotoxin shock. The inhibitory action of Rap1b on PI3K signaling may be mediated by activation of phosphatase SHP-1. Thus, this study reveals an unexpected role for Rap1b as a key suppressor of neutrophil migration and lung inflammation.

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