Ontogeny of Big endothelin-1 effects in newborn piglet pulmonary vasculature

1993 ◽  
Vol 265 (1) ◽  
pp. H139-H145 ◽  
Author(s):  
S. Liben ◽  
D. J. Stewart ◽  
J. De Marte ◽  
T. Perreault
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Vasculature ◽  
Converting Enzyme ◽  
Endothelin 1 ◽  
Amino Acid Peptide ◽  
Eta Receptor ◽  
Eta Receptor Antagonist ◽  
Dose Dependent

Endothelin-1 (ET-1), a 21-amino acid peptide produced by endothelial cells, results from the cleavage of preproendothelin, generating Big ET-1, which is then cleaved by the ET-converting enzyme (ECE) to form ET-1. Big ET-1, like ET-1, is released by endothelial cells. Big ET-1 is equipotent to ET-1 in vivo, whereas its vasoactive effects are less in vitro. It has been suggested that the effects of Big ET-1 depend on its conversion to ET-1. ET-1 has potent vasoactive effects in the newborn pig pulmonary circulation, however, the effects of Big ET-1 remain unknown. Therefore, we studied the effects of Big ET-1 in isolated perfused lungs from 1- and 7-day-old piglets using the ECE inhibitor, phosphoramidon, and the ETA receptor antagonist, BQ-123Na. The rate of conversion of Big ET-1 to ET-1 was measured using radioimmunoassay. ET-1 (10(-13) to 10(-8) M) produced an initial vasodilation, followed by a dose-dependent potent vasoconstriction (P < 0.001), which was equal at both ages. Big ET-1 (10(-11) to 10(-8) M) also produced a dose-dependent vasoconstriction (P < 0.001). The constrictor effects of Big ET-1 and ET-1 were similar in the 1-day-old, whereas in the 7-day-old, the constrictor effect of Big ET-1 was less than that of ET-1 (P < 0.017).(ABSTRACT TRUNCATED AT 250 WORDS)

In vitro and in vivo effects of endothelin-1 and YM598, a selective endothelin ETA receptor antagonist, on the lower urinary tract

2008 ◽  
Vol 580 (3) ◽  
pp. 394-400 ◽  
Author(s):  
Masashi Ukai ◽  
Hironori Yuyama ◽  
Akira Fujimori ◽  
Akiko Koakutsu ◽  
Masanao Sanagi ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Receptor Antagonist ◽  
Lower Urinary Tract ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
Eta Receptor Antagonist ◽  
In Vivo Effects ◽  
Lower Urinary

Endothelin-1 inhibits endothelium-dependent vasodilatation in the human forearm: reversal by ETA receptor blockade in patients with atherosclerosis

2002 ◽  
Vol 102 (3) ◽  
pp. 321-327 ◽  
Author(s):  
Felix BÖHM ◽  
Gunvor AHLBORG ◽  
John PERNOW
Keyword(s):  
Endothelial Dysfunction ◽  
Venous Occlusion ◽  
Similar Degree ◽  
Receptor Blockade ◽  
Arterial Infusion ◽  
Endothelin 1 ◽  
Enhanced Expression ◽  
Eta Receptor ◽  
Eta Receptor Antagonist

Several cardiovascular disorders, including atherosclerosis, are associated with endothelial dysfunction and enhanced expression of endothelin-1 (ET-1). The role of ET-1 in the development of endothelial dysfunction in vivo remains unclear. The objective of the present study was to investigate the effect of elevated circulating levels of ET-1 on endothelium-dependent vasodilatation (EDV), and to test the hypothesis that ETA receptor antagonism improves EDV in patients with atherosclerosis. EDV and endothelium-independent vasodilatation were determined by brachial artery infusion of acetylcholine and sodium nitroprusside respectively during measurement of forearm blood flow (FBF) with venous occlusion plethysmography. A 60min intra-arterial infusion of ET-1 (n = 10) significantly blunted EDV in young healthy males (33±13% compared with 271±74% increase in FBF induced by 10μg/min acetylcholine; P < 0.01). Noradrenaline, which evoked a similar degree of vasoconstriction, did not attenuate EDV. In a separate set of experiments, a 60min intra-arterial infusion of the selective ETA receptor antagonist BQ123 evoked a significant increase in EDV in patients with atherosclerosis (n = 10; 109±45% compared with 255±101% increase in FBF induced by 10μg/min acetylcholine; P < 0.01), whereas no significant change was observed in healthy age-matched controls (n = 9). Endothelium-independent vasodilatation was not affected by ET-1 or BQ123. These observations demonstrate that elevated levels of ET-1 impair EDV in healthy control subjects. Furthermore, ETA receptor blockade improves EDV in patients with atherosclerosis, indicating that ET-1 attenuates EDV via an ETA-receptor-mediated mechanism.

Vessel- and target cell-specific actions of endothelin-1 and endothelin-3 in rat liver

1995 ◽  
Vol 269 (2) ◽  
pp. G269-G277 ◽  
Author(s):  
J. X. Zhang ◽  
M. Bauer ◽  
M. G. Clemens
Keyword(s):  
Endothelial Cells ◽  
Kupffer Cells ◽  
Hepatic Microcirculation ◽  
Ito Cells ◽  
Endothelin 1 ◽  
Latex Beads ◽  
Eta Receptor ◽  
Eta Receptor Antagonist ◽  
Endothelin 3 ◽  
Rat Livers

We studied the sinusoidal and extrasinusoidal constrictor response of hepatic microcirculation to endothelin-1 (ET-1) and endothelin-3 (ET-3) and the possible role of Ito cells vs. Kupffer cells or endothelial cells in mediating this response, using isolated rat livers under high-power intravital microscopy. Rats were pretreated by injection of 2.6 x 10(8) fluorescent latex beads (1 micron) intravenously to label Kupffer cells. Three hours later livers were isolated and perfused before and during the infusion of 1 nM ET-1 or ET-3 with or without the endothelin type A (ETA) receptor antagonist BQ-123 or ETB antagonist IRL-1038. Alternatively, the perfused livers were infused with the ETB agonist sarafotoxin 6c (S6c, 1 or 5 nM). Sinusoid diameters were quantitated at the sites of Ito cells (identified by vitamin A fluorescence) or Kupffer cells (phagocytosed fluorescent latex beads) or where neither cell type was found (endothelial cells). ET-1 was found to induce significant sinusoid constriction at the sites of Ito cells (13.21 +/- 0.58 microns control vs. 10.47 +/- 0.48 microns during ET-1 infusion) but not at the sites of Kupffer cells or endothelial cells (13.26 +/- 0.79 vs. 12.92 +/- 0.61 microns and 12.20 +/- 0.71 vs. 11.98 +/- 0.40 microns, respectively), whereas neither ET-3 nor S6c had any effect on sinusoid narrowing, despite a 1.8-fold (ET-3) or 5.6-fold (5 nM S6c) greater increase in total portal resistance compared with ET-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract 408: Endothelin-1 and Vitamin D 3 Potentiated Calcification and Outward Vascular Remodeling in Leptin-deficient ob/ob Mice

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Luciana S Carmo ◽  
Youri E Almeida ◽  
Maria C Andrade ◽  
Elisangela F Silva ◽  
Marcel Liberman
Keyword(s):  
Vitamin D ◽  
Vascular Calcification ◽  
Vascular Remodeling ◽  
Diabetic Patients ◽  
Internal Elastic Lamina ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
Vitamin D 3

Vascular remodeling, which is an adaptive response of the vessel to specific stimuli has a pivotal role in cardiovascular disease, such as aneurysm formation. In that scope, serum endothelin-1 (ET-1) which is increased in diabetic patients, may contribute to atherosclerosis and aneurysm development. We hypothesized that leptin-deficient ob/ob mice may demonstrate an exaggerated vascular remodeling associated with vascular calcification after Vitamin D 3 in vivo . We further investigated the role of ET-1 in vascular smooth muscle cells (SMC) osteochondrogenic differentiation and calcification in vitro . We used leptin-deficient (obob, n=12) and C57BL/6 mice (C57, n=12) injected with saline (Cont) or Vitamin D 3 8x10 4 IU (VitD) i.p. daily for 14 days. Results are shown as Mean±SEM and considered statistically significant if p≤.05 by ANOVA. Aorta from ob/obVitD increased both external and internal elastic lamina circumferential length (3478±269.7μm and 3186±262.6μm) versus (vs.) ob/obCont (2841±74.73μm and 2657±71.37μm) vs. C57VitD (2611±39.62μm and 2333±41.79μm) and vs. C57Cont (2569±164.6μm and 2351±167.7μm), thus characterizing outward vascular remodeling. We found that vascular calcification area strongly correlated with increased total vessel area (r 2 =0.8, p=0.003). We also incubated primary SMC isolated either from obob or from C57 aorta without (Cont) or with ET-1 50nM (ET) for 0-72h. ObobET SMC increased calcification vs. obobCont (1,69±0.025 vs. 1.03±0.03) after 14 days p<.05, n=3 and C57ET did not calcify (0.97±0.02 vs. C57Cont 1±0.05), p=NS. Concomitantly, obobET SMC increased osteochondrogenic differentiation, by modulating RUNX2 (1.23±0.03 vs. obobCont 1±0.01, p<.05 n=3) after 48h, which did not occur in C57. Furthermore, ERk1/2 dephosphorylation peaked after 30min in C57ET in comparison to 60min in obobET SMC. Concurrently, VitD increased both ETA and ETB receptor (4.00±1.04 and 4.25±1.25) in obob aorta vs. paired control in vivo . Nevertheless, C57VitD increased ETA receptor mRNA expression (5.44±1.08) only. In conclusion, we uncovered signaling pathways that may connect Vitamin D and ET-1 calcifying effect to induce excessive outward remodeling in type 2 diabetes.

Carcinoembryonic Antigen (CEA) Regulates Tumor-Angiogenesis in Colon Carcinomas.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1897-1897
Author(s):  
Kira Braemswig ◽  
Marina Poettler ◽  
Wazlawa Kalinowska ◽  
Christoph Zielinski ◽  
Gerald W Prager
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Tumor Angiogenesis ◽  
Endothelial Cell Proliferation ◽  
Erk Phosphorylation ◽  
Dose Dependent Increase ◽  
Dose Dependent

Abstract Human carcinoembryonic antigen (CEA) is a cell surface adhesion molecule member of the Immunoglobulin Superfamily (IgSF). Aberrant upregulation and secretion of soluble CEA is a common feature found in a wide variety of human cancers such as colon, breast and lung. Previous in vitro and in vivo results have demonstrated that CEA can affect tumor cell behavior including the inhibition of cell differentiation and apoptosis. However, any functional effects on angiogenic endothelial cell behavior are so far unknown. In the present work we found that in endothelial cells exogenous CEA led to a time and dose dependent increase in ERK phosphorylation, which was inhibited by the specific MEK inhibitor U0126. Thereby, the observed CEA effect was comparable in time and intense with the canonical angiogenic growth factor VEGF. The CEA-induced ERK phosphorylation was not affected by the blockage of VEGFR-2 / flk-1 using a specific inhibiting peptide (CBO-P11), which indicates a VEGF-independent mechanism. Furthermore, co-stimulation of endothelial cells with VEGF and CEA shows synergistic effects on ERK phosphorylation. While in endothelial cells no endogenous expression of CEA is detected, its putative receptor, the CEA receptor (CEAR), is highly expressed as shown by immunohistochemical staining of paraffin-embedded colon carcinoma sections as well as in biochemical analyses. When an activating antibody against CEAR was used, CEA-induced ERK phosphorylation was mimicked, while downregulation of CEAR by siRNA diminished CEA-induced signal transduction, significantly. To test a biological relevance of our findings, we first measured endothelial cell proliferation: CEA led to a dose dependent increase in endothelial cell proliferation in vitro, which again revealed a synergistic effect with VEGF. Thereby, CEA-induced endothelial cell proliferation was again independent of VEGFR-2 / flk-1. A biological role of CEA in tumor-angiogenesis was reflected by an in vivo model using CEA Mimotope immunized BALB/c mice, which were transplanted with MethA/CEA overexpressing tumor cells. Immunohistological analyses of these tumors revealed a significantly reduced vascular density, which was accompanied with diminished tumor growth. Our data provide first evidence of CEA as a novel pro-angiogenic activator of endothelial cells, which results in an increase in endothelial cell proliferation, independent of VEGFR-2. Furthermore, by targeting CEA in an in vivo mouse model, tumor-angiogenesis was markley reduced, indicating a potential therapeutic target in cancer.

Heparin Induces Synthesis and Secretion of Tissue Factor Pathway Inhibitor from Endothelial Cells In Vitro

2000 ◽  
Vol 83 (06) ◽  
pp. 937-943 ◽  
Author(s):  
Birgit Svensson ◽  
Randi Olsen ◽  
Mirella Ezban ◽  
Bjarne Østerud ◽  
Ruth Paulssen ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Surface Membrane ◽  
Molecular Size ◽  
Fold Increase ◽  
Coagulation System ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Stimulation Of

SummaryTFPI is a potent inhibitor of the extrinsic coagulation system constitutively synthesized by endothelial cells. A major portion of intravascular TFPI is stored associated with endothelial cells, and administration of unfractionated heparin (UFH) in vivo causes a prompt mobilization of TFPI into the circulation. The present study was conducted to investigate how UFH affected the synthesis, secretion and anticoagulant potency of TFPI in endothelial cells in vitro. A spontaneously transformed immortal endothelial cell line was used (ECV304). Stimulation of ECV304 cells with UFH caused a prompt dose-dependent (0-5 IU UFH/ml) release of TFPI to the medium accompanied by no change of TFPI at the surface membrane assessed by immunocytochemical methods. Northern blot analysis revealed two mRNA transcripts for TFPI with a molecular size of 1.4 kb and 4.4 kb, respectively. Stimulation of ECV304 cells for 24 hrs with various concentrations of UFH caused a dose-dependent increase of TFPI in the medium (6.2-29.6 ng/106 cells within the concentration range 0-10 IU/ml). A similar dose-dependent increase in the expression of both TFPI mRNA species was observed. Long-term incubation of ECV304 cells with 5.0 IU/ml UFH caused a 5-10 fold increase in the TFPI concentration accumulated in the medium over 48 hrs. The increased TFPI mRNA expression induced by UFH appeared already after 10 min, peaked after 2-4 hrs, remained augmented throughout the entire period of UFH exposure, and preceeded the synthesis-dependent increase in TFPI release by 2-4 hrs. The procoagulant activity of the cells was downregulated by 36 % and the contribution of TFPI to the anticoagulant potency of ECV304 cells was moderately increased after 24 hrs heparin stimulation. It is suggested that these mechanisms are of major importance for the anticoagulant function of heparins.

Endothelial cells internalize monoclonal antibody to angiotensin-converting enzyme

1996 ◽  
Vol 270 (5) ◽  
pp. L704-L713 ◽  
Author(s):  
V. R. Muzykantov ◽  
E. N. Atochina ◽  
A. Kuo ◽  
E. S. Barnathan ◽  
K. Notarfrancesco ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Endothelial Cells ◽  
Angiotensin Converting Enzyme ◽  
Umbilical Vein ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
Affinity Constant ◽  
Converting Enzyme

We investigated the fate of MAb 9B9, a monoclonal antibody to angiotensin-converting enzyme (ACE), which binds to endothelium both in vitro and in vivo. Using cultured human umbilical vein endothelial cells (HUVEC) and isolated perfused rat lungs (IPL), we demonstrated specific and saturable binding of 125I-labeled MAb 9B9 at 4 degrees C [affinity constant (Kd) = 20-50 nM, maximal number of binding sites (Bmax) = 1.5-3.0 x 10(5) sites/cell]. When 125I-MAb 9B9 was bound to HUVEC at 37 degrees C, only 40% of cell-associated radioactivity was acid elutable, suggesting antibody internalization. This was confirmed by finding that 1) the amount of MAb 9B9 uptake at 37 degrees C was higher than at 4 degrees C both in HUVEC and IPL; 2) binding of 125I-labeled streptavidin with HUVEC and IPL pretreated with biotinylated MAb 9B9 (b-MAb 9B9) was diminished in a temperature- and time-dependent fashion at 37 degrees C; and 3) b-MAb 9B9 bound to HUVEC at 37 degrees C was found intracellularly by ultrastructural analysis using streptavidin gold. Intracellular 125I-MAb 9B9 was found in microsomal fractions of lung homogenate from IPL and after intravenous (iv) injections in rats. Degradation of internalized MAb 9B9 was minimal, since > 90% of cell-associated 125I label remained precipitable by trichloracetic acid in HUVEC, IPL, and in vivo. Autoradiography of sodium dodecyl sulfate-polyacrylamide gel electrophoresis of lung homogenates made as late as several days after iv injections of 125I-MAb 9B9 in rats demonstrated a predominant band above 140 kDa. These data indicate that endothelial cells either in vitro or in vivo internalize the ACE ligand MAb 9B9 without significant intracellular degradation. Therefore MAb 9B9 may be useful for selective intracellular delivery of drugs to the pulmonary vascular endothelium after systemic administration.

scholarly journals Autocrine effects of endothelin-1 on leukocyte-endothelial interaction: stimulation of endothelin B receptor subtype reduces endothelial adhesiveness via a nitric oxide-dependent mechanism

Blood ◽  
1996 ◽  
Vol 88 (10) ◽  
pp. 3894-3900 ◽  
Author(s):  
T Murohara ◽  
AM Lefer
Keyword(s):  
Nitric Oxide ◽  
Receptor Antagonist ◽  
Receptor Subtype ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Endothelin B ◽  
Eta Receptor Antagonist ◽  
Inhibition Of Thrombin

The effects of endothelin-1 (ET-1) on P-selectin-mediated leukocyte endothelial interaction were examined in vitro. Adherence of autologous polymorphonuclear leukocytes (PMNs) to the endothelium was markedly enhanced by endothelial stimulation with either (2 U/mL) thrombin, (1 mumol/L) histamine, or (100 nmol/L) phorbol myristate acetate (PMA). In contrast, ET-1 alone (10 and 100 nmol/L) only slightly increased the number of adhering PMNs. The increased PMN adherence to thrombin- or histamine-stimulated endothelium, which was blocked by an anti-P-selectin monoclonal antibody, was also significantly attenuated by preincubation of coronary segments with (100 nmol/L) ET-1. We further investigated the mechanism of this anti-adherence action of ET-1 on thrombin-stimulated endothelial adhesiveness. Preincubation of coronary segments with a selective ETA receptor antagonist, BQ485 (1 mumol/L), had no effect on ET-1 inhibition of thrombin-induced PMN adherence. In contrast, preincubation with a selective ETB receptor antagonist, BQ788 (1 mumol/L) significantly reversed ET-1 inhibition of thrombin-induced PMN adherence, whereas the selective ETB receptor agonist BQ-3020 mimicked the inhibitory action of ET-1 on thrombin-induced PMN adherence. Furthermore, (100 mumol/L) N omega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, significantly attenuated ET-1 inhibition of thrombin-stimulated PMN adherence. These results suggest that ET-1 may inhibit P-selectin-mediated leukocyte-endothelial interaction via ETB receptor stimulation and subsequent endothelial NO formation. This autocrine effect of ET-1 may be involved in pathophysiologic states such as early atherogenesis by preventing leukocyte-endothelial interaction in constricted blood vessels.

Interaction among ET-1, endothelium-derived nitric oxide, and prostacyclin in pulmonary arteries and veins

1994 ◽  
Vol 267 (1) ◽  
pp. H139-H147 ◽  
Author(s):  
T. M. Zellers ◽  
J. McCormick ◽  
Y. Wu
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Veins ◽  
Pulmonary Arteries ◽  
Endothelin 1 ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Potent Vasoconstrictor ◽  
Eta Receptor Antagonist ◽  
Arteries And Veins

Endothelin-1 causes vasodilation of the intact porcine pulmonary vascular bed. To determine the cause of this vasodilation, we investigated the interactions of endothelin-1 (ET-1), endothelium-derived nitric oxide (EDNO), and prostacyclin in isolated small porcine pulmonary arteries and veins under in vitro conditions. ET-1 caused concentration-dependent contractions in arteries and veins, augmented by the nitric oxide synthase (NOS) inhibitor, N omega-nitro-L-arginine, in pulmonary veins. BQ-123 (ETA-receptor antagonist) depressed the ET-1-induced contractions. Sarafotoxin S6C, an ETB-receptor agonist, caused contractions of pulmonary veins only. Endothelium-dependent relaxations to bradykinin and ET-1 were greater in pulmonary veins compared with arteries, inhibited by N omega-nitro-L-arginine, and reversed by L-arginine. BQ-123 augmented ET-1-induced arterial relaxation. ET-3 and sarafotoxin S6C, ETB-receptor agonists, caused comparable endothelium-dependent relaxations in arteries and veins. ET-1 caused a fourfold greater increase in prostacyclin release in pulmonary veins compared with arteries. We conclude that ET-1 is a potent vasoconstrictor of porcine pulmonary vessels and stimulates the release of EDNO and prostacyclin, which oppose the contractions to the peptide. The release of these endothelium-derived vasodilators appears greater in pulmonary veins.

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