scholarly journals Vascular Dysfunction in Malaria: Understanding the Role of the Endothelial Glycocalyx

2021 ◽  
Vol 9 ◽  
Author(s):  
Margaret A. Bush ◽  
Nicholas M. Anstey ◽  
Tsin W. Yeo ◽  
Salvatore M. Florence ◽  
Donald L. Granger ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Blood Perfusion ◽  
Endothelial Activation ◽  
Cellular Adhesion ◽  
Adverse Outcomes ◽  
Endothelial Glycocalyx ◽  
Nitric Oxide Signaling

Malaria caused by Plasmodium falciparum results in over 400,000 deaths annually, predominantly affecting African children. In addition, non-falciparum species including vivax and knowlesi cause significant morbidity and mortality. Vascular dysfunction is a key feature in malaria pathogenesis leading to impaired blood perfusion, vascular obstruction, and tissue hypoxia. Contributing factors include adhesion of infected RBC to endothelium, endothelial activation, and reduced nitric oxide formation. Endothelial glycocalyx (eGC) protects the vasculature by maintaining vessel integrity and regulating cellular adhesion and nitric oxide signaling pathways. Breakdown of eGC is known to occur in infectious diseases such as bacterial sepsis and dengue and is associated with adverse outcomes. Emerging studies using biochemical markers and in vivo imaging suggest that eGC breakdown occurs during Plasmodium infection and is associated with markers of malaria disease severity, endothelial activation, and vascular function. In this review, we describe characteristics of eGC breakdown in malaria and discuss how these relate to vascular dysfunction and adverse outcomes. Further understanding of this process may lead to adjunctive therapy to preserve or restore damaged eGC and reduce microvascular dysfunction and the morbidity/mortality of malaria.

Endothelial Heparan Sulfate Proteoglycans in Sepsis: The Role of the Glycocalyx

2021 ◽  
Vol 47 (03) ◽  
pp. 274-282
Author(s):  
Kaori Oshima ◽  
Samantha I. King ◽  
Sarah A. McMurtry ◽  
Eric P. Schmidt
Keyword(s):  
Heparan Sulfate ◽  
Vascular Function ◽  
Platelet Adhesion ◽  
Vascular Dysfunction ◽  
Heparan Sulfate Proteoglycans ◽  
Endothelial Glycocalyx ◽  
Endothelial Surface ◽  
Mechanistic Investigation

AbstractThere is increasing recognition of the importance of the endothelial glycocalyx and its in vivo manifestation, the endothelial surface layer, in vascular homeostasis. Heparan sulfate proteoglycans (HSPGs) are a major structural constituent of the endothelial glycocalyx and serve to regulate vascular permeability, microcirculatory tone, leukocyte and platelet adhesion, and hemostasis. During sepsis, endothelial HSPGs are shed through the induction of “sheddases” such as heparanase and matrix metalloproteinases, leading to loss of glycocalyx integrity and consequent vascular dysfunction. Less well recognized is that glycocalyx degradation releases HSPG fragments into the circulation, which can shape the systemic consequences of sepsis. In this review, we will discuss (1) the normal, homeostatic functions of HSPGs within the endothelial glycocalyx, (2) the pathological changes in HSPGs during sepsis and their consequences on the local vascular bed, and (3) the systemic consequences of HSPG degradation. In doing so, we will identify potential therapeutic targets to improve vascular function during sepsis as well as highlight key areas of uncertainty that require further mechanistic investigation.

Abstract 1138: Endogenous Adipocyte-Derived Factors Diminish Coronary Endothelial-Dependent Vasodilation Via Inhibition Of Nitric Oxide Synthase

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Gregory A Payne ◽  
Lena Borbouse ◽  
Gregory M Dick ◽  
Johnathan D Tune
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Nitric Oxide Synthase ◽  
Coronary Blood Flow ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Dependent Manner ◽  
Pericardial Adipose Tissue ◽  
Oxide Synthase

Adipocytokines may be the molecular link between obesity and vascular disease; however, effects of these factors on coronary vascular function have not been delineated. Accordingly, this study was designed to examine mechanisms by which endogenous adipocyte-derived factors impair coronary endothelial-dependent vasodilation in vivo . Experiments were conducted in open-chest anesthetized dogs (n = 16) before and during treatment with endogenous adipocyte-derived factors. Phosphate buffered saline was conditioned in a shaking water bath with parietal pericardial adipose tissue (3 g/ml) for 30 min at 37°C. The conditioned buffer was then filtered (0.2 μm) and infused directly into the coronary circulation (0.3 ml/min). Conditioned buffer did not significantly affect baseline coronary blood flow (0.50 ± 0.01 vs. 0.61 ± 0.05 ml/min/g, p = 0.68), mean arterial pressure (103 ± 6 vs. 96 ± 9 mmHg, p = 0.74), or heart rate (87 ± 13 vs. 110 ± 24 beats/min, p = 0.44). Conditioned buffer had no effect on responses to intracoronary angiotensin II (2.5 – 750 ng; 74 vs. 70% vasoconstriction). Under control conditions, bradykinin (0.03 – 3 μg/min) increased coronary blood flow (303 ± 65%) to 2.02 ± 0.31 ml/min/g in a dose-dependent manner. Conditioned buffer attenuated maximum bradykinin vasodilation to 1.64 ± 0.26 ml/min/g (167 ± 33% increase; p < 0.05). This decrease in endothelial-dependent dilation was not due to increases in superoxide production, as administration of the superoxide dismutase mimetic Tempol (10 mg/min, ic) did not improve bradykinin vasodilation (120 ± 27% increase; p < 0.05). Inhibition of nitric oxide synthase with L-NAME (150 μg/min, ic) reduced maximum bradykinin vasodilation to 0.93 ± 0.04 ml/min/g (p < 0.05) and endogenous adipocyte-derived factors had no further inhibitory effect (0.82 ± 0.09 ml/min/g, p = 0.24). These data indicate that endogenous adipocyte-derived factors diminish endothelial-dependent coronary vasodilation via inhibition of nitric oxide synthase rather than a reduction in nitric oxide bioavailability by superoxide. Our findings importantly link endogenous adipocyte-derived factors with pro-atherogenic coronary vascular dysfunction in vivo .

scholarly journals Diphlorethohydroxycarmalol Isolated from Ishige okamurae Exerts Vasodilatory Effects via Calcium Signaling and PI3K/Akt/eNOS Pathway

2021 ◽  
Vol 22 (4) ◽  
pp. 1610 ◽  
Author(s):  
Yu An Lu ◽  
Yunfei Jiang ◽  
Hye-Won Yang ◽  
Jin Hwang ◽  
You-Jin Jeon ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Transgenic Zebrafish ◽  
No Production ◽  
Protective Effects ◽  
In Vivo Experiments ◽  
Vasodilatory Effect ◽  
Ishige Okamurae

Nitric oxide (NO) is released by endothelial cells in the blood vessel wall to enhance vasodilation. Marine polyphenols are known to have protective effects against vascular dysfunction and hypertension. The present study is the first to investigate how diphlorethohydroxycarmalol (DPHC) isolated from Ishige okamurae affects calcium levels, resulting in enhanced vasodilation. We examined calcium modulation with the well-known receptors, acetylcholine receptor (AchR) and vascular endothelial growth factor 2 (VEGFR2), which are related to NO formation, and further confirmed the vasodilatory effect of DPHC. We confirmed that DPHC stimulated NO production by increasing calcium levels and endothelial nitric oxide synthase (eNOS) expression. DPHC affected AchR and VEGFR2 expression, thereby influencing transient calcium intake. Specific antagonists, atropine and SU5416, were used to verify our findings. Furthermore, based on the results of in vivo experiments, we treated Tg(flk:EGFP) transgenic zebrafish with DPHC to confirm its vasodilatory effect. In conclusion, the present study showed that DPHC modulated calcium transit through AchR and VEGFR2, increasing endothelial-dependent NO production. Thus, DPHC, a natural marine component, can efficiently ameliorate cardiovascular diseases by improving vascular function.

scholarly journals Endothelial dysfunction and body mass index: is there a role for plasma peroxynitrite?

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Theresa Chikopela ◽  
Douglas C. Heimburger ◽  
Longa Kaluba ◽  
Pharaoh Hamambulu ◽  
Newton Simfukwe ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Body Mass ◽  
Vascular Function ◽  
Aortic Ring ◽  
Normal Weight ◽  
Oxide Synthase ◽  
Weight Groups

Abstract Background Endothelial function is dependent on the balance between vasoconstrictive and vasodilatory substances. The endothelium ability to produce nitric oxide is one of the most crucial mechanisms in regulating vascular tone. An increase in inducible nitric oxide synthase contributes to endothelial dysfunction in overweight persons, while oxidative stress contributes to the conversion of nitric oxide to peroxynitrite (measured as nitrotyrosine in vivo) in underweight persons. The objective of this study was to elucidate the interaction of body composition and oxidative stress on vascular function and peroxynitrite. This was done through an experimental design with three weight groups (underweight, normal weight and overweight), with four treatment arms in each. Plasma nitrotyrosine levels were measured 15–20 h post lipopolysaccharide (LPS) treatment, as were aortic ring tension changes. Acetylcholine (ACh) and sodium nitroprusside (SNP) challenges were used to observe endothelial-dependent and endothelial-independent vascular relaxation after pre-constriction of aortic rings with phenylephrine. Results Nitrotyrosine levels in saline-treated rats were similar among the weight groups. There was a significant increase in nitrotyrosine levels between saline-treated rats and those treated with the highest lipopolysaccharide doses in each of the weight groups. In response to ACh challenge, Rmax (percentage reduction in aortic tension) was lowest in overweight rats (112%). In response to SNP, there was an insignificantly lower Rmax in the underweight rats (106%) compared to the normal weight rats (112%). Overweight rats had a significant decrease in Rmax (83%) in response to SNP, signifying involvement of a more chronic process in tension reduction changes. A lower Rmax accompanied an increase in peroxynitrite after acetylcholine challenge in all weight groups. Conclusions Endothelial dysfunction, observed as an impairment in the ability to reduce tension, is associated with increased plasma peroxynitrite levels across the spectrum of body mass. In higher-BMI rats, an additional role is played by vascular smooth muscle in the causation of endothelial dysfunction.

S-nitroso-albumin carries a thiol-labile pool of nitric oxide, which causes venodilation in the rat

2005 ◽  
Vol 289 (2) ◽  
pp. H916-H923 ◽  
Author(s):  
Nelson N. Orie ◽  
Patrick Vallance ◽  
Dean P. Jones ◽  
Kevin P. Moore
Keyword(s):  
Nitric Oxide ◽  
Molecular Weight ◽  
Blood Flow ◽  
Vascular Function ◽  
Low Molecular Weight ◽  
Aortic Blood Flow ◽  
Hemodynamic Effects ◽  
Rapid Decomposition ◽  
Aortic Blood

It is now established that S-nitroso-albumin (SNO-albumin) circulates at low nanomolar concentrations under physiological conditions, but concentrations may increase to micromolar levels during disease states (e.g., cirrhosis or endotoxemia). This study tested the hypothesis that high concentrations of SNO-albumin observed in some diseases modulate vascular function and that it acts as a stable reservoir of nitric oxide (NO), releasing this molecule when the concentrations of low-molecular-weight thiols are increased. SNO-albumin was infused into rats to increase the plasma concentration from <50 nmol/l to ∼4 μmol/l. This caused a 29 ± 6% drop in blood pressure, 20 ± 4% decrease in aortic blood flow, and a 25 ± 14% reduction of renal blood flow within 10 min. These observations were in striking contrast to those of an infused arterial vasodilator (hydralazine), which increased aortic blood flow, and suggested that SNO-albumin acts primarily as a venodilator in vivo. This was confirmed by the observations that glyceryl trinitrate (a venodilator) led to similar hemodynamic changes and that the hemodynamic effects of SNO-albumin are reversed by infusion of colloid. Infusion of N-acetylcysteine into animals with artificially elevated plasma SNO-albumin concentrations led to the rapid decomposition of SNO-albumin in vivo and reproduced the hemodynamic effects of SNO-albumin infusion. These data demonstrate that SNO-albumin acts primarily as a venodilator in vivo and represents a stable reservoir of NO that can release NO when the concentrations of low-molecular-weight thiols are elevated.

Abstract 14820: Sirt7 Deficiency in Blood Vessel Components Impairs Vascular Function by Inhibiting Cell Cycle- and Inflammatory-Related Protein Expression

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Yuichi Kimura ◽  
Yasuhiro Izumiya ◽  
Satoshi Araki ◽  
Satoru Yamamura ◽  
Yoshiro Onoue ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Blood Flow ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Vascular Diseases ◽  
Tube Formation ◽  
Hindlimb Ischemia ◽  
Proliferation Assay

Introduction: Aging is a well-established cardiovascular risk factor and associated with vascular dysfunction. Sirt7, one of the members of mammalian sirtuin family, is thought to be involved in age-related diseases. However, little is known about the relative contribution of Sirt7 in vascular dysfunction. Hypothesis: Sirt7 maintains vascular cell functions and its deficiency plays a critical role in vascular diseases. Methods: Sirt7 loss- and gain-of-function experiments were performed with human aortic smooth muscle cells (HAoSMCs) and human umbilical vein endothelial cells (HUVECs). In vivo, blood flow recovery was evaluated by hindlimb ischemia model in homozygous Sirt7 deficient (Sirt7-/-) and wild-type (WT) mice. Irradiated WT mice were intravenously received bone marrow (BM) cells from WT or Sirt7 -/- mouse to achieve BM transfer. Results: An RNAi-medicated Sirt7 knockdown resulted in a significant inhibition of HAoSMCs proliferation following serum or Platelet-derived growth factor BB (PDGF-BB) stimulation as determined by cell count, BrdU cell proliferation assay and MTS proliferation assay. Knockdown of endogenous Sirt7 also reduced cell migration as revealed by Boyden chamber migration assay. The Cyclin D1 and Cyclin dependent kinase 2 (CDK2) protein levels were significantly decreased in Sirt7 siRNA-treated HAoSMCs in response to serum or PDGF-BB stimulation. In endothelial cells, knockdown of Sirt7 attenuated tube formation, proliferation and migration. These changes were accompanied by reduced ERK activation and VCAM-1 mRNA and protein expression in Sirt7 siRNA-treated HUVECs. Conversely, overexpression of Sirt7 by adenovirus enhanced tube formation and cell proliferation. In vivo, blood flow recovery in response to hindlimb ischemia was significantly attenuated in Sirt7-/- mice compared with WT mice. There was no difference in blood flow recovery between WT mice transplanted with WT or Sirt7-/- BM cells suggesting that Sirt7 deficiency in vascular cells have a predominant effect on attenuated blood flow recovery in response to hindlimb ischemia. Conclusions: Sirt7 in blood vessel components have an important role in maintenance of vascular function. Sirt7 could be a promising therapeutic target for vascular diseases.

Endothelin-mediated in vivo pressor responses following TRPV1 activation

2011 ◽  
Vol 301 (3) ◽  
pp. H1135-H1142 ◽  
Author(s):  
Vahagn A. Ohanyan ◽  
Giacinta Guarini ◽  
Charles K. Thodeti ◽  
Phani K. Talasila ◽  
Priya Raman ◽  
...  
Keyword(s):  
Vascular Function ◽  
Vascular Reactivity ◽  
Transient Receptor Potential ◽  
Vascular Dysfunction ◽  
Vascular Complications ◽  
Receptor Potential ◽  
Immunoblot Analysis ◽  
Trpv1 Channels ◽  
Transient Receptor

Transient receptor potential vanilliod 1 (TRPV1) channels have recently been postulated to play a role in the vascular complications/consequences associated with diabetes despite the fact that the mechanisms through which TRPV1 regulates vascular function are not fully known. Accordingly, our goal was to define the mechanisms by which TRPV1 channels modulate vascular function and contribute to vascular dysfunction in diabetes. We subjected mice lacking TRPV1 [TRPV1(−/−)], db/ db, and control C57BLKS/J mice to in vivo infusion of the TRPV1 agonist capsaicin or the α-adrenergic agonist phenylephrine (PE) to examine the integrated circulatory actions of TRPV1. Capsaicin (1, 10, 20, and 100 μg/kg) dose dependently increased MAP in control mice (5.7 ± 1.6, 11.7 ± 2.1, 25.4 ± 3.4, and 51.6 ± 3.9%), which was attenuated in db/db mice (3.4 ± 2.1, 3.9 ± 2.1, 7.0 ± 3.3, and 17.9 ± 6.2%). TRPV1(−/−) mice exhibited no changes in MAP in response to capsaicin, suggesting the actions of this agonist are specific to TRPV1 activation. Immunoblot analysis revealed decreased aortic TRPV1 protein expression in db/db compared with control mice. Capsaicin-induced responses were recorded following inhibition of endothelin A and B receptors (ETA /ETB). Inhibition of ETA receptors abolished the capsaicin-mediated increases in MAP. Combined antagonism of ETA and ETB receptors did not further inhibit the capsaicin response. Cultured endothelial cell exposure to capsaicin increased endothelin production as shown by an endothelin ELISA assay, which was attenuated by inhibition of TRPV1 or endothelin-converting enzyme. TRPV1 channels contribute to the regulation of vascular reactivity and MAP via production of endothelin and subsequent activation of vascular ETA receptors. Impairment of TRPV1 channel function may contribute to vascular dysfunction in diabetes.

Effects of NG-substituted arginines on coronary vascular function after endotoxin

1993 ◽  
Vol 75 (1) ◽  
pp. 424-431 ◽  
Author(s):  
M. J. Winn ◽  
B. Vallet ◽  
N. K. Asante ◽  
S. E. Curtis ◽  
S. M. Cain
Keyword(s):  
Nitric Oxide ◽  
Vascular Function ◽  
Endotoxic Shock ◽  
No Synthase ◽  
Relaxing Factor ◽  
Nos Inhibitors ◽  
Nos Inhibitor ◽  
Endothelium Derived Relaxing Factor ◽  
Constrictor Response

We investigated the responses of canine coronary rings to endothelium-derived relaxing factor-nitric oxide- (EDRF-NO) dependent agonists and NO synthase (NOS) inhibitors 3 h after endotoxic shock was induced in dogs by lipopolysaccharide infusion (LPS; 2 mg/kg). EDRF-NO-dependent relaxation to thrombin [control maximum response produced after administration of thrombin (Emax) was -85.2 +/- 7.0% of the constrictor response produced by the thromboxane analogue U-46619], acetylcholine (control Emax -88.4 +/- 3.4%), or bradykinin (control Emax -80.5 +/- 2.2%) was not inhibited by LPS (Emax thrombin -75.9 +/- 9.5%; Emax acetylcholine -90.2 +/- 2.4%; Emax bradykinin -91.6 +/- 3.4%). The NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) (10(-6)-3 x 10(-4) M) caused constriction of rings with endothelium (Emax 36.3 +/- 5.6%), an effect that was greater after LPS (Emax 59.2 +/- 4.1%; P < 0.05). D-NMMA had no effect in control, but it increased tension after LPS (Emax 20.8 +/- 9.7%). Contrary to expectations, L- and D-NMMA relaxed endothelium-denuded rings (-30.4 +/- 8.7% L-NMMA; -45.1 +/- 11.7% D-NMMA; P < 0.05). However, neither agent caused relaxation after in vivo LPS (10.2 +/- 3.4% L-NMMA; 8.9 +/- 5.2% D-NMMA). N omega-nitro-L-arginine-methylester (L-NAME) and nitro-L-arginine (10(-6)-3 x 10(-4) M) increased tension (Emax 82.3 +/- 23.9 and 73.1 +/- 8.8%, respectively) but only when endothelium was present, and the increases were no greater in LPS-treated groups than in controls (with LPS: Emax L-NAME 87.3 +/- 16.5%; Emax nitro-L-arginine 65.7 +/- 3.3%).(ABSTRACT TRUNCATED AT 250 WORDS)

AIDS-related vasculopathy: evidence for oxidative and inflammatory pathways in murine and human AIDS

2005 ◽  
Vol 289 (4) ◽  
pp. H1373-H1380 ◽  
Author(s):  
Reshma S. Baliga ◽  
Alysia A. Chaves ◽  
Liang Jing ◽  
Leona W. Ayers ◽  
John A. Bauer
Keyword(s):  
Nitric Oxide ◽  
Vascular Dysfunction ◽  
Endothelial Activation ◽  
Time Dependent ◽  
Nitric Oxide Donor ◽  
Intercellular Adhesion Molecule ◽  
Maximal Response ◽  
Vascular Tissues ◽  
Murine Aids ◽  
Hiv Aids

Increased life expectancy of human immunodeficiency virus (HIV)-positive patients has led to evidence of complications apparently not directly related to immunodeficiency or opportunistic infection, including increased cardiovascular risk. We tested the hypothesis that vascular dysfunction occurs in the murine acquired immune deficiency syndrome (AIDS) model and evaluated potential mechanisms in murine AIDS tissues and relevant human HIV/AIDS vascular tissues. We also investigated endothelial activation and/or endothelial protein nitration and their association with time-dependent vascular dysfunction. At 1 and 5 wk of murine AIDS, statistically significant decreases in KCl contractility and time-dependent contractile deficits in response to phenylephrine were observed. The maximal response (Emax) was reduced by ∼40% at 10 wk, and EC50 values were significantly changed: 102 ± 7.3 ng for control vs. 190 ± 37 and 130 ± 22 ng at 5 and 10 wk, respectively ( P < 0.05). Endothelium-dependent relaxation to ACh was decreased (EC50 = 120 ± 27 and 343 ± 94 nM for control and at 10 wk, respectively), whereas the response to an exogenous nitric oxide donor, sodium nitroprusside, remained unchanged, suggesting a specific endothelial dysfunction. Histochemical investigations of the same vascular tissues as well as corresponding coronary endothelium showed an increase in protein 3-nitrotyrosine, intercellular adhesion molecule, and nitric oxide synthase isoforms 2 and 3. These findings were corroborated in concurrent experiments in a cohort of well-cataloged human cardiac microvascular tissues. We have demonstrated, for the first time, a specific functional vasculopathy with endothelial involvement in a murine model of AIDS that was also associated with and correlated to increased oxidative stress and specific endothelial activation. This finding was echoed in a relevant population of human HIV/AIDS patients. Research into sources and intracellular targets of oxidants in this disease could provide important mechanistic insights and may reveal new therapeutic opportunities for this increasingly important cardiovascular disease state.

Sign in / Sign up

Export Citation Format

Share Document