Chylomicron-remnant-like particles modify production of vasoactive mediators by endothelial cells

2004 ◽  
Vol 32 (1) ◽  
pp. 110-112 ◽  
Author(s):  
M. Evans ◽  
Y. Berhane ◽  
K.M. Botham ◽  
J. Elliott ◽  
C.P.D. Wheeler-Jones
Keyword(s):  
Endothelial Cell ◽  
Cell Function ◽  
Endothelial Cell Function ◽  
Cell Dysfunction ◽  
Vasoactive Mediators ◽  
Prostanoid Production ◽  
Cox 2 ◽  
Chylomicron Remnants ◽  
Oxide Synthase ◽  
Prostacyclin Synthesis

Endothelial-cell dysfunction is a critical initiating event in the pathogenesis of atherosclerosis. Although there is evidence to suggest that chylomicron remnants (CMRs), lipoproteins derived from the diet, influence endothelial-cell function to generate a pro-atherogenic phenotype, the mechanisms involved remain undefined. We have examined the effects of CMR-like particles (CMR-LPs) on human endothelial-cell function, focusing on the cyclo-oxygenase (COX) and nitric oxide synthase (NOS) pathways. CMR-LPs strongly enhanced the expression of the inducible cyclo-oxygenase COX-2 and increased prostacyclin synthesis in a biphasic manner. Studies with the COX-2-selective inhibitor NS-398 confirmed the COX-2 dependency of the later increase in prostanoid production. Pre-incubation with CMR-LPs reduced basal and thrombin-stimulated cGMP generation, whereas expression of endothelial NOS was not modified by remnant treatment.

scholarly journals Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia

2017 ◽  
Vol 232 (1) ◽  
pp. R27-R44 ◽  
Author(s):  
D S Boeldt ◽  
I M Bird
Keyword(s):  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Cell Function ◽  
Endothelial Cell Dysfunction ◽  
Hypertensive Disorders Of Pregnancy ◽  
Endothelial Cell Function ◽  
Vascular Adaptation ◽  
Cell Dysfunction ◽  
Maternal Adaptation ◽  
Flow Through

Maternal vascular adaptation to pregnancy is critically important to expand the capacity for blood flow through the uteroplacental unit to meet the needs of the developing fetus. Failure of the maternal vasculature to properly adapt can result in hypertensive disorders of pregnancy such as preeclampsia (PE). Herein, we review the endocrinology of maternal adaptation to pregnancy and contrast this with that of PE. Our focus is specifically on those hormones that directly influence endothelial cell function and dysfunction, as endothelial cell dysfunction is a hallmark of PE. A variety of growth factors and cytokines are present in normal vascular adaptation to pregnancy. However, they have also been shown to be circulating at abnormal levels in PE pregnancies. Many of these factors promote endothelial dysfunction when present at abnormal levels by acutely inhibiting key Ca2+ signaling events and chronically promoting the breakdown of endothelial cell–cell contacts. Increasingly, our understanding of how the contributions of the placenta, immune cells, and the endothelium itself promote the endocrine milieu of PE is becoming clearer. We then describe in detail how the complex endocrine environment of PE affects endothelial cell function, why this has contributed to the difficulty in fully understanding and treating this disorder, and how a focus on signaling convergence points of many hormones may be a more successful treatment strategy.

scholarly journals Methylglyoxal triggers human aortic endothelial cell dysfunction via modulation of the KATP/MAPK pathway

2019 ◽  
Vol 317 (1) ◽  
pp. C68-C81 ◽  
Author(s):  
Yihan Wang ◽  
Leo M. Hall ◽  
Marisa Kujawa ◽  
Hainan Li ◽  
Xiang Zhang ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Network Formation ◽  
Cell Function ◽  
Mapk Pathway ◽  
Endothelial Cell Dysfunction ◽  
Endothelial Cell Function ◽  
Cell Dysfunction ◽  
Type 2 Diabetic

Endothelial dysfunction is a key risk factor in diabetes-related multiorgan damage. Methylglyoxal (MGO), a highly reactive dicarbonyl generated primarily as a by-product of glycolysis, is increased in both type 1 and type 2 diabetic patients. MGO can rapidly bind with proteins, nucleic acids, and lipids, resulting in structural and functional changes. MGO can also form advanced glycation end products (AGEs). How MGO causes endothelial cell dysfunction, however, is not clear. Human aortic endothelial cells (HAECs) from healthy (H-HAECs) and type 2 diabetic (D-HAECs) donors were cultured in endothelial growth medium (EGM-2). D-HAECs demonstrated impaired network formation (on Matrigel) and proliferation (MTT assay), as well as increased apoptosis (caspase-3/7 activity and TUNEL staining), compared with H-HAECs. High glucose (25 mM) or AGEs (200 ng/ml) did not induce such immediate, detrimental effects as MGO (10 µM). H-HAECs were treated with MGO (10 µM) for 24 h with or without the ATP-sensitive potassium (KATP) channel antagonist glibenclamide (1 µM). MGO significantly impaired H-HAEC network formation and proliferation and induced cell apoptosis, which was reversed by glibenclamide. Furthermore, siRNA against the KATP channel protein Kir6.1 significantly inhibited endothelial cell function at basal status but rescued impaired endothelial cell function upon MGO exposure. Meanwhile, activation of MAPK pathways p38 kinase, c-Jun NH2-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) (determined by Western blot analyses of their phosphorylated forms, p-JNK, p-p38, and p-ERK) in D-HAECs were significantly enhanced compared with those in H-HAECs. MGO exposure enhanced the activation of all three MAPK pathways in H-HAECs, whereas glibenclamide reversed the activation of p-stress-activated protein kinase/JNK induced by MGO. Glyoxalase-1 (GLO1) is the endogenous MGO-detoxifying enzyme. In healthy mice that received an inhibitor of GLO1, MGO deposition in aortic wall was enhanced and endothelial cell sprouting from isolated aortic segment was significantly inhibited. Our data suggest that MGO triggers endothelial cell dysfunction by activating the JNK/p38 MAPK pathway. This effect arises partly through activation of KATP channels. By understanding how MGO induces endothelial dysfunction, our study may provide useful information for developing MGO-targeted interventions to treat vascular disorders in diabetes.

Dissociation of endothelial cell dysfunction and blood pressure in SHR

1995 ◽  
Vol 269 (1) ◽  
pp. H189-H194 ◽  
Author(s):  
B. Tesfamariam ◽  
M. L. Ogletree
Keyword(s):  
Blood Pressure ◽  
Endothelial Cell ◽  
Cell Function ◽  
Receptor Activation ◽  
Endothelial Cell Dysfunction ◽  
Endothelial Cell Function ◽  
Cell Dysfunction ◽  
Tp Receptor ◽  
Wistar Kyoto ◽  
Endothelium Dependent Relaxation

This study was designed to examine the impairment of endothelium-dependent relaxation in spontaneously hypertensive rats (SHR), to determine whether endothelial cell function is normalized by in vivo treatment with a thromboxane A2-prostaglandin endoperoxide (TP)-receptor blocker, and to establish whether endothelial dysfunction contributes to the elevated blood pressure. In isolated aortic rings from SHR, endothelium-dependent relaxations caused by acetylcholine, adenosine diphosphate, and alpha-thrombin were markedly impaired compared with those from Wistar-Kyoto (WKY) normotensive rats. Arachidonic acid-induced contractions were significantly enhanced in aorta from SHR. In contrast, relaxations caused by direct smooth muscle vasodilators, nitroprusside and cromakalim, and contractions caused by U-46619 were not different between SHR and WKY rats. Treatment of SHR with the oral TP-receptor antagonist, ifetroban, at 20 and 50 mg.kg-1.day-1 fully restored endothelium-dependent relaxation toward normal. However, ifetroban produced no effect on blood pressure in SHR. In vitro incubation of aortic rings from SHR with ifetroban also normalized relaxations to acetylcholine but had no effect in aorta from WKY. In contrast, the thromboxane A synthase inhibitor, dazoxiben, only partially improved abnormal acetylcholine-induced relaxations in aorta from SHR. The results demonstrate that endothelial cell dysfunction in hypertension can be restored to normal by selective TP-receptor blockade. Furthermore, endothelial cell dysfunction and TP-receptor activation may not significantly contribute to elevated systemic blood pressure in SHR.

scholarly journals Adiponectin Promotes Revascularization of Ischemic Muscle through a Cyclooxygenase 2-Dependent Mechanism

2009 ◽  
Vol 29 (13) ◽  
pp. 3487-3499 ◽  
Author(s):  
Koji Ohashi ◽  
Noriyuki Ouchi ◽  
Kaori Sato ◽  
Akiko Higuchi ◽  
Tomo-o Ishikawa ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Function ◽  
Vascular Diseases ◽  
Adaptor Protein ◽  
Cyclooxygenase 2 ◽  
Endothelial Cell Migration ◽  
Endothelial Cell Function ◽  
Vascular Insufficiency ◽  
Cox 2

ABSTRACT Adiponectin is a fat-derived plasma protein that has cardioprotective roles in obesity-linked diseases. Because cyclooxygenase 2 (COX-2) is an important modulator of endothelial function, we investigated the possible contribution of COX-2 to adiponectin-mediated vascular responses in a mouse hind limb model of vascular insufficiency. Ischemic insult increased COX-2 expression in endothelial cells of wild-type mice, but this induction was attenuated in adiponectin knockout mice. Ischemia-induced revascularization was impaired in mice in which the Cox-2 gene is deleted in Tie2-Cre-expressing cells. Adenovirus-mediated overexpression of adiponectin enhanced COX-2 expression and revascularization of ischemic limbs in control mice, but not in targeted Cox-2-deficient mice. In cultured endothelial cells, adiponectin protein increased COX-2 expression, and ablation of COX-2 abrogated the adiponectin-stimulated increases in endothelial cell migration, differentiation, and survival. Ablation of calreticulin (CRT) or its adaptor protein CD91 diminished adiponectin-stimulated COX-2 expression and endothelial cell responses. These observations provide evidence that adiponectin promotes endothelial cell function through CRT/CD91-mediated increases in COX-2 signaling. Thus, disruption of the adiponectin-COX-2 regulatory axis in endothelial cells could participate in the pathogenesis of obesity-related vascular diseases.

scholarly journals Endothelin-1-induced endothelial microvesicles impair endothelial cell function

2020 ◽  
Vol 128 (6) ◽  
pp. 1497-1505
Author(s):  
L. Madden Brewster ◽  
Vinicius P. Garcia ◽  
Ma’ayan V. Levy ◽  
Kelly A. Stockelman ◽  
Anabel Goulding ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cell Function ◽  
Atherosclerotic Vascular Disease ◽  
Vascular Effects ◽  
Endothelial Cell Function ◽  
Endothelin 1 ◽  
Potent Vasoconstrictor ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide released by the endothelium that contributes to the regulation of vascular tone. Overexpression of ET-1 has been implicated in the etiology of atherosclerotic vascular disease. Endothelial cell-derived microvesicles (EMVs) play a pivotal role in vascular health and disease. Their functional phenotype is largely dictated by the stimulus for release. EMVs released in response to various pathological conditions have been shown to elicit deleterious vascular effects. In the present study, we determined, in vitro, the effect of ET-1 on EMV release from endothelial cells and the effects of ET-1-generated EMVs on endothelial cell inflammation, apoptosis, and endothelial nitric oxide synthase (eNOS). ET-1 induced a marked increase in EMV release. ET-1-generated EMVs significantly increased endothelial cell inflammation and reduced eNOS protein expression and activation. Moreover, the endothelial effects of ET-1-derived EMVs were similar to the direct effects of ET-1. ET-1-generated EMVs may contribute to the proatherogenic profile of ET-1.

scholarly journals The influence of chylomicron remnants on endothelial cell function in the isolated perfused rat aorta

1998 ◽  
Vol 139 (2) ◽  
pp. 273-282 ◽  
Author(s):  
David J Grieve ◽  
Michael A Avella ◽  
Jonathan Elliott ◽  
Kathleen M Botham
Keyword(s):  
Endothelial Cell ◽  
Cell Function ◽  
Rat Aorta ◽  
Endothelial Cell Function ◽  
Chylomicron Remnants

Endothelial cell dysfunction occurs very early following trauma-hemorrhage and persists despite fluid resuscitation

1993 ◽  
Vol 265 (3) ◽  
pp. H973-H979 ◽  
Author(s):  
P. Wang ◽  
Z. F. Ba ◽  
I. H. Chaudry
Keyword(s):  
Endothelial Cell ◽  
Fluid Resuscitation ◽  
Cell Function ◽  
Endothelial Cell Dysfunction ◽  
Cellular Functions ◽  
Midline Laparotomy ◽  
Endothelial Cell Function ◽  
Shed Blood ◽  
Cell Dysfunction ◽  
Significant Difference

Although hemorrhage produces alterations in hemodynamics and cellular functions, it remains unknown if endothelial cell function is depressed in a nonheparinized model of trauma-hemorrhage and resuscitation. To study this, rats underwent a 5-cm midline laparotomy (i.e., trauma induced) and were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of maximal bleed-out volume was returned in the form of Ringer lactate (RL). They were then resuscitated with four times the volume of the shed blood with RL over 60 min. At the time of maximal bleed out (approximately 50 min from the onset of hemorrhage), 1.5, and 4 h after the completion of resuscitation, aortic rings (approximately 2.5 mm in length) were isolated and mounted in organ chambers. Dose responses for an endothelium-dependent vasodilator (acetylcholine) and endothelium-independent vasodilator (nitroglycerin) were determined. The results indicate that endothelium-dependent relaxation was depressed at the time of maximal bleed out and persisted even after resuscitation. However, there was no significant difference in nitroglycerin-induced relaxation at any point during the study period. In addition, hypoxia-induced contraction, a process mediated by endothelium-derived contracting factor, decreased significantly following hemorrhage and resuscitation. Thus endothelial cell dysfunction (i.e., reduced release of endothelium-derived relaxing and contracting factors) occurs very early after trauma-hemorrhage and persists despite fluid resuscitation.

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