scholarly journals Regulation of sFlt-1 and VEGF secretion by adenosine under hypoxic conditions in rat placental villous explants

2010 ◽  
Vol 299 (6) ◽  
pp. R1629-R1633 ◽  
Author(s):  
Eric M. George ◽  
Kathy Cockrell ◽  
Thomas H. Adair ◽  
Joey P. Granger
Keyword(s):  
Vascular Tissue ◽  
Placental Tissue ◽  
Vegf Receptor ◽  
Extracellular Adenosine ◽  
Adenosine Receptor Antagonist ◽  
Hypoxic Conditions ◽  
Important Regulator ◽  
Antiangiogenic Factors ◽  
Placental Ischemia

The role of adenosine in the regulation of cardiovascular function has long been acknowledged, but only recently has its importance in angiogenesis been appreciated, most notably, through its direct regulation of the proangiogenic growth factor, VEGF. Recent work has established that proangiogenic and antiangiogenic factors, specifically VEGF and and the soluble VEGF receptor fms-like tyrosine kinase-1 (sFlt-1), are directly influenced by hypoxia in placental ischemia. While adenosine has been reported to be an important regulator of VEGF in vascular tissue, the importance of adenosine in regulating VEGF and sFlt-1 in placental tissue is unclear. Here, we have investigated the role of adenosine in the secretion of VEGF and the antiangiogenic protein sFlt-1 in placental villous explants. Under normoxic conditions (6% oxygen), the nonspecific adenosine receptor antagonist, 8-sulphophenyltheophylline (8-SPT) had no effect on either VEGF ( P = 0.38) or sFlt-1 ( P = 0.56) secretion. However, under hypoxic conditions (1% oxygen), 8-SPT attenuated the increase in the secretion of both VEGF and sFlt-1 ( P < 0.05 and P < 0.005, respectively). Exogenous and the adenosine transporter inhibitor dipyridamole (which increases extracellular levels of adenosine) showed differential effects under normoxic conditions: sFlt-1 levels in media increased significantly ( P < 0.05), whereas VEGF was unaffected ( P = 0.67 and P = 0.19, respectively). These data indicate that extracellular adenosine can regulate VEGF and sFlt-1 secretion in the hypoxic placenta and could, therefore, control the balance of these competing angiogenic factors in diseases characterized by placental ischemia.

Abstract 269: 5-aminoimidazole-4-carboxamide-3-ribonucleoside (AICAR) Decreases Soluble Fms-like Tyrosine Kinase-1 (sFlt-1) and Attenuates Endoplasmic Reticulum Stress in Rat Placental Villi Explants

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Christopher T Banek ◽  
Haley E Gillham ◽  
Sarah M Johnson ◽  
Hans C Dreyer ◽  
Jeffrey S Gilbert
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
De Novo ◽  
Vegf Receptor ◽  
Sprague Dawley ◽  
Hypoxic Conditions ◽  
Ampk Phosphorylation ◽  
Angiogenic Balance ◽  
Placental Villi ◽  
Placental Ischemia

Preeclampsia, defined by the onset of de novo hypertension and proteinuria near the 20th week of gestation, is a major contributor to maternal and fetal morbidity and mortality worldwide. Preeclampsia is often preceded by placental ischemia and an imbalance in circulating angiogenic factors (e.g. VEGF - vascular endothelial growth factor, sFlt-1 - soluble VEGF receptor 1). Recent studies also report increased expression of endoplasmic reticulum (ER) stress products in preeclamptic placentas. Our laboratory recently reported 5-aminoimidazole-4-carboxamide-3-ribonuceloside (AICAR) reduces blood pressure and improves angiogenic balance (increased VEGF, decreased sFlt-1) in rats with placental ischemia-induced hypertension, but the mechanism is unclear. We hypothesized AICAR would decrease sFlt-1, increase AMPK phosphorylation, and decrease ER stress in hypoxic placental villous explants. On day 19 of pregnancy, placentas were isolated from four Sprague-Dawley rats and immediately dissected in ice-cold phosphate-buffered saline. Explants were cultured for 12 hours in physiologic normoxic (8% O2) and hypoxic (1.5% O2) conditions. All experiments were performed in triplicate. VEGF secretion was unaffected by AICAR treatment in both normoxic and hypoxic conditions. AICAR decreased sFlt -1 secretion in hypoxic villi (2147±116 vs. *1411±67, P<0.05). Additionally, AMPK activation ratio was increased with AICAR, and was hypoxic-dependent (8%: 2.9±0.3; 8%+A: 3.3±0.1; 1.5%: 3.5±0.1; 1.5%+A: *4.5±0.01;*P<.05). Moreover, markers of ER stress were increased with hypoxia, and decreased with AICAR treatment (BiP 8%: 1.2±0.2; 8%+A: 1.0±0.0; 1.5%: *8.3±0.7; 1.5%+A: 1.9±0.0.3;*P<.05), (CHOP 8%: 0.5±0.0; 8%+A: 0.3±0.1; 1.5%: *1.7±0.1; 1.5%+A: 0.7±0.1;*P<.05). ATF4 was not changed with hypoxia or AICAR treatment. The present data show that AICAR stimulates AMPK phosphorylation and decreases ER stress response proteins in hypoxic placental villi. Further, the present data support the hypothesis that AICAR restores angiogenic balance by decreasing sFlt-1 rather than increasing VEGF secretion from placental villi. These findings suggest AICAR may improve placental function during pregnancies complicated by placental-ischemia.

scholarly journals Beneficial and detrimental role of adenosine signaling in diseases and therapy

2015 ◽  
Vol 119 (10) ◽  
pp. 1173-1182 ◽  
Author(s):  
Hong Liu ◽  
Yang Xia
Keyword(s):  
Disease Progression ◽  
Tissue Injury ◽  
Acute Stage ◽  
Therapeutic Effects ◽  
Extracellular Adenosine ◽  
Hypoxic Conditions ◽  
Substantial Progress ◽  
Disease Stages ◽  
Adenosine Signaling

Adenosine is a major signaling nucleoside that orchestrates cellular and tissue adaptation under energy depletion and ischemic/hypoxic conditions by activation of four G protein-coupled receptors (GPCR). The regulation and generation of extracellular adenosine in response to stress are critical in tissue protection. Both mouse and human studies reported that extracellular adenosine signaling plays a beneficial role during acute states. However, prolonged excess extracellular adenosine is detrimental and contributes to the development and progression of various chronic diseases. In recent years, substantial progress has been made to understand the role of adenosine signaling in different conditions and to clarify its significance during the course of disease progression in various organs. These efforts have and will identify potential therapeutic possibilities for protection of tissue injury at acute stage by upregulation of adenosine signaling or attenuation of chronic disease progression by downregulation of adenosine signaling. This review is to summarize current progress and the importance of adenosine signaling in different disease stages and its potential therapeutic effects.

scholarly journals Role of adenosine in functional recovery following anoxic coma in Locusta migratoria

2019 ◽  
Author(s):  
Rachel A. Van Dusen ◽  
Christopher Lanz ◽  
R. Meldrum Robertson
Keyword(s):  
Functional Recovery ◽  
Locusta Migratoria ◽  
Metabolic Stress ◽  
Extracellular Adenosine ◽  
Adenosine Receptor Antagonist ◽  
Spreading Depolarization ◽  
Downstream Effects ◽  
Rate Of Recovery ◽  
Anoxic Coma

AbstractWhen exposed to prolonged anoxia insects enter a reversible coma during which neural and muscular systems temporarily shut down. Nervous system shut down is a result of spreading depolarization throughout neurons and glial cells. Upon return to normoxia, recovery occurs following the restoration of ion gradients. However, there is a delay in the functional recovery of synaptic transmission following membrane repolarization. In mammals, the build-up of extracellular adenosine following spreading depolarization contributes to this delay. Adenosine accumulation is a marker of metabolic stress and it has many downstream effects through the activation of adenosine receptors. Here we demonstrate that adenosine lengthens the time to functional recovery following anoxic coma in locusts. Caffeine, used as an adenosine receptor antagonist, decreased the time to recovery in intact animals and lengthened the time to recovery in semi-intact animals. Our results show that the rate of recovery in insect systems is affected by the presence of adenosine.

Role of adenosine in hypoxic alterations of anaphylaxis of isolated guinea pig hearts

1989 ◽  
Vol 257 (5) ◽  
pp. H1378-H1388
Author(s):  
L. J. Heller ◽  
G. J. Trachte ◽  
J. F. Regal
Keyword(s):  
Guinea Pig ◽  
Vascular Resistance ◽  
Adenosine Receptor ◽  
Guinea Pigs ◽  
Adenosine Release ◽  
Adenosine Receptor Antagonist ◽  
Isolated Hearts ◽  
Hypoxic Conditions ◽  
Intracardiac Injection

Previous studies suggest that high levels of adenosine may enhance histamine release and contribute to atrioventricular (AV) nodal conduction arrhythmias during anaphylaxis of isolated guinea pig hearts. To determine whether elevations in endogenous adenosine evoked by hypoxic conditions have similar effects, isolated hearts of guinea pigs passively sensitized by intracardiac injection were perfused with solutions equilibrated with 95% O2 (normoxia) or 30% O2 (hypoxia). When compared with normoxia, hypoxia before antigen challenge increased adenosine release, decreased vascular resistance, and prolonged P-R intervals, whereas hypoxia during anaphylaxis potentiated the increase in adenosine release, attenuated the increases in vascular resistance and atrial rate, and increased the occurrence of conduction arrhythmias without altering the antigen-induced release of either histamine or thromboxane. Addition of the adenosine receptor antagonist 8-(4-sulfophenyl)theophylline (SP-T) to the hypoxic perfusate significantly decreased antigen-induced release of histamine and thromboxane. These data indicate that 1) hypoxia-induced depression of antigen-induced mediator release may be counteracted by the stimulatory effect of the increased adenosine induced by hypoxia, and 2) under hypoxic conditions, adenosine's negative dromotropic, chronotropic, and vasodilatory effects may influence the anaphylactic reaction.

Immunology and Pathology in Ocular Drug Development

2021 ◽  
pp. 019262332097839
Author(s):  
Meg Ferrell Ramos ◽  
Jacqueline Brassard ◽  
Sharmila Masli
Keyword(s):  
Foreign Protein ◽  
Clear Vision ◽  
Antiangiogenic Factors ◽  
Intraocular Drug Delivery ◽  
Delayed Rejection ◽  
Destructive Inflammation ◽  
Allogenic Tissue ◽  
Tissue Grafts ◽  
Immunosuppressive Cells

Clear vision is dependent on features that protect the anatomical integrity of the eye (cornea and sclera) and those that contribute to internal ocular homeostasis by conferring hemangiogenic (avascular tissues and antiangiogenic factors), lymphangiogenic (lack of draining lymphatics), and immunologic (tight junctions that form blood–ocular barriers, immunosuppressive cells, and modulators) privileges. The later examples are necessary components that enable the eye to maintain an immunosuppressive environment that responds to foreign invaders in a deviated manner, minimizing destructive inflammation that would impair vision. These conditions allowed for the observations made by Medawar, in 1948, of delayed rejection of allogenic tissue grafts in the anterior chamber of mouse eye and permit the sequestration of foreign invaders (eg, Toxoplasma gondii) within the retina of healthy individuals. Yet successful development of intraocular drugs (biologics and delivery devices) has been stymied by adverse ocular pathology, much of which is driven by immune pathways. The eye can be intolerant of foreign protein irrespective of delivery route, and endogenous ocular cells have remarkable plasticity when recruited to preserve visual function. This article provides a review of current understanding of ocular immunology and the potential role of immune mechanisms in pathology observed with intraocular drug delivery.

scholarly journals The Role of 5-Lipoxygenase and Leukotrienes in Shock and Ischemia-Reperfusion Injury

2007 ◽  
Vol 7 ◽  
pp. 56-74 ◽  
Author(s):  
Antonietta Rossi ◽  
Carlo Pergola ◽  
Salvatore Cuzzocrea ◽  
Lidia Sautebin
Keyword(s):  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Biological Activities ◽  
Ischemia Reperfusion ◽  
Targeted Disruption ◽  
Pathological Conditions ◽  
Metabolic Products ◽  
Important Regulator ◽  
Multicellular Organisms

The leukotrienes (LTs) are metabolic products of arachidonic acid via the 5-lipoxygenase (5-LO) pathway. The biological activities of LTs suggest that they are mediators of acute inflammatory and immediate hypersensitivity responses. In particular, the 5-LO activation has been proposed to be an important regulator for pathogenesis in multicellular organisms. The role of LTs in tissue damage, associated with septic and nonseptic shock and ischemia-reperfusion, has been extensively studied by the use of 5-LO inhibitors, receptor antagonists, and mice with a targeted disruption of the 5-LO gene (5-LOKO). In particular, several data indicate that LTs regulate neutrophil trafficking in damaged tissue in shock and ischemia-reperfusion, mainly through the modulation of adhesion molecule expression. This concept may provide new insights into the interpretation of the protective effect of 5-LO inhibition, which may be useful in the therapy of pathological conditions associated with septic and nonseptic shock and ischemia-reperfusion injury.

scholarly journals Role of the extracellular cAMP-adenosine pathway in renal physiology

2001 ◽  
Vol 281 (4) ◽  
pp. F597-F612 ◽  
Author(s):  
Edwin K. Jackson ◽  
Raghvendra K. Dubey
Keyword(s):  
Adenosine Receptors ◽  
Epithelial Transport ◽  
Receptor Activation ◽  
Hormonal Control ◽  
Renal Physiology ◽  
Tight Coupling ◽  
Extracellular Adenosine ◽  
Mediated Effects ◽  
Extracellular Camp

Adenosine exerts physiologically significant receptor-mediated effects on renal function. For example, adenosine participates in the regulation of preglomerular and postglomerular vascular resistances, glomerular filtration rate, renin release, epithelial transport, intrarenal inflammation, and growth of mesangial and vascular smooth muscle cells. It is important, therefore, to understand the mechanisms that generate extracellular adenosine within the kidney. In addition to three “classic” pathways of adenosine biosynthesis, contemporary studies are revealing a novel mechanism for renal adenosine production termed the “extracellular cAMP-adenosine pathway.” The extracellular cAMP-adenosine pathway is defined as the egress of cAMP from cells during activation of adenylyl cyclase, followed by the extracellular conversion of cAMP to adenosine by the serial actions of ecto-phosphodiesterase and ecto-5′-nucleotidase. This mechanism of extracellular adenosine production may provide hormonal control of adenosine levels in the cell-surface biophase in which adenosine receptors reside. Tight coupling of the site of adenosine production to the site of adenosine receptors would permit a low-capacity mechanism of adenosine biosynthesis to have a large impact on adenosine receptor activation. The purposes of this review are to summarize the physiological roles of adenosine in the kidney; to describe the classic pathways of renal adenosine biosynthesis; to review the evidence for the existence of the extracellular cAMP-adenosine pathway; and to describe possible physiological roles of the extracellular cAMP-adenosine pathway, with particular emphasis on the kidney.

scholarly journals Placental ischemia-stimulated T-helper 17 cells induce preeclampsia-associated cytolytic natural killer cells during pregnancy

2018 ◽  
Vol 315 (2) ◽  
pp. R336-R343 ◽  
Author(s):  
Corbin A. Shields ◽  
Maggie McCalmon ◽  
Tarek Ibrahim ◽  
Dakota L. White ◽  
Jan M. Williams ◽  
...  
Keyword(s):  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Natural Killer ◽  
Cell Activation ◽  
Fetal Weight ◽  
T Helper ◽  
T Helper 17 ◽  
Placental Ischemia ◽  
In Pregnancy

Previous studies have demonstrated that T-helper 17 (TH17) cells and cytolytic natural killer (cNK) cells are increased in women with preeclampsia. In this study we investigated the role of placental ischemia-stimulated TH17 cells in induction of cNK cells in pregnancy. We further assessed the role of TH17 cell-mediated oxidative stress in facilitation of cNK cell activation in pregnancy by treating rats with the SOD mimetic tempol. CD4+/CD25− cells were isolated from reduced uterine perfusion pressure (RUPP) rats and differentiated into TH17 cells in vitro. On day 12 of gestation ( GD12), 1 × 106 placental ischemia-stimulated TH17 cells were injected into normal pregnant (NP) rats (NP + RUPP TH17 rats), and a subset of rats were treated with tempol (30 mg·kg−1·day−1) from GD12 to GD19 (NP + RUPP TH17 + tempol rats). On GD19, cNK cells, mean arterial pressure, fetal weight, and cNK cell-associated cytokines and proteins were measured. Placental cNK cells were 2.9 ± 1, 14.9 ± 4, and 2.8 ± 1.0% gated in NP, NP + RUPP TH17, and NP + RUPP TH17 + tempol rats, respectively. Mean arterial pressure increased from 96 ± 5 mmHg in NP rats to 118 ± 2 mmHg in NP + RUPP TH17 rats and was 102 ± 3 mmHg in NP + RUPP TH17 + tempol rats. Fetal weight was 2.37 ± 0.04, 1.95 ± 0.14, and 2.3 ± 0.05 g in NP, NP + RUPP TH17, and NP + RUPP TH17 + tempol rats, respectively. Placental IFNγ increased from 1.1 ± 0.6 pg/mg in NP rats to 3.9 ± 0.6 pg/mg in NP + RUPP TH17 rats. Placental perforin increased from 0.18 ± 0.18 pg/mg in NP rats to 2.4 ± 0.6 pg/mg in NP + RUPP TH17 rats. Placental levels of granzymes A and B followed a similar pattern. Treatment with tempol did not lower placental cNK cytokines or proteins. The results of the present study identify TH17 cells as a mediator of aberrant NK cell activation that is associated with preeclampsia.

Evidence for a functional calcium-sensing receptor that modulates myogenic tone in rat subcutaneous small arteries

2005 ◽  
Vol 288 (4) ◽  
pp. H1756-H1762 ◽  
Author(s):  
Jacqueline Ohanian ◽  
Kelly M. Gatfield ◽  
Donald T. Ward ◽  
Vasken Ohanian
Keyword(s):  
Vascular Tissue ◽  
Immunoblot Analysis ◽  
Negative Regulator ◽  
Intraluminal Pressure ◽  
Myogenic Tone ◽  
Internal Diameter ◽  
Calcium Sensing Receptor ◽  
Small Arteries ◽  
Calcium Sensing

Myogenic tone of small arteries is dependent on the presence of extracellular calcium ([Formula: see text]), and, recently, a receptor that senses changes in Ca2+, the calcium-sensing receptor (CaR), has been detected in vascular tissue. We investigated whether the CaR is involved in the regulation of myogenic tone in rat subcutaneous small arteries. Immunoblot analysis using a monoclonal antibody against the CaR demonstrated its presence in rat subcutaneous arteries. To determine whether the CaR was functionally active, segments of artery (<250 μm internal diameter) mounted in a pressure myograph with an intraluminal pressure of 70 mmHg were studied after the development of myogenic tone. Increasing [Formula: see text] concentration ([Ca2+]o) cumulatively from 0.5 to 10 mM induced an initial constriction (0.5–2 mM) followed by dilation (42 ± 5% loss of tone). The dose-dependent dilation was mimicked by other known CaR agonists including magnesium (1–10 mM) and the aminoglycosides neomycin (0.003–10 mM) and kanamycin (0.003–3 mM). PKC activation with the phorbol ester phorbol-12,13-dibutyrate (20nM) inhibited the dilation induced by high [Ca2+]o or neomycin, whereas inhibition of PKC with GF109203X (10 μM) increased the responses to [Formula: see text] or neomycin, consistent with the role of PKC as a negative regulator of the CaR. We conclude that rat subcutaneous arteries express a functionally active CaR that may be involved in the modulation of myogenic tone and hence the regulation of peripheral vascular resistance.

scholarly journals The mechano-sensitive response of β1 integrin promotes SRC-positive late endosome recycling and activation of Yes-associated protein

2020 ◽  
Vol 295 (39) ◽  
pp. 13474-13487
Author(s):  
Marc R. Block ◽  
Molly Brunner ◽  
Théo Ziegelmeyer ◽  
Dominique Lallemand ◽  
Mylène Pezet ◽  
...  
Keyword(s):  
Late Endosome ◽  
Cell Periphery ◽  
Β1 Integrin ◽  
Nonreceptor Tyrosine Kinase ◽  
Cell Contractility ◽  
Late Endosomes ◽  
Important Regulator ◽  
Nuclear Shuttling ◽  
Endosomal System

Yes-associated protein (YAP) signaling has emerged as a crucial pathway in several normal and pathological processes. Although the main upstream effectors that regulate its activity have been extensively studied, the role of the endosomal system has been far less characterized. Here, we identified the late endosomal/lysosomal adaptor MAPK and mTOR activator (LAMTOR) complex as an important regulator of YAP signaling in a preosteoblast cell line. We found that p18/LAMTOR1-mediated peripheral positioning of late endosomes allows delivery of SRC proto-oncogene, nonreceptor tyrosine kinase (SRC) to the plasma membrane and promotes activation of an SRC-dependent signaling cascade that controls YAP nuclear shuttling. Moreover, β1 integrin engagement and mechano-sensitive cues, such as external stiffness and related cell contractility, controlled LAMTOR targeting to the cell periphery and thereby late endosome recycling and had a major impact on YAP signaling. Our findings identify the late endosome recycling pathway as a key mechanism that controls YAP activity and explains YAP mechano-sensitivity.

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