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PubMedDate not supplied

Inferior canine hindlimb ischemia and reperfusion impairs femoral artery endothelium-dependent wall relaxation.

This experimental investigation was carried out to study the endothelium-dependent ischemia-reperfusion injury upon the release of nitric oxide (NO) in the canine femoral artery. The tested experimental model was the inferior canine hindlimb ischemia induced by infrarenal abdominal aortic clamping followed by reperfusion. The research protocol was standardized in four experimental groups (n=6): (1) Control group; (2) Ischemia (120 minutes) group; (3) Ischemia (90 minutes) and reperfusion (60 minutes) group; and (4) Ischemia (120 minutes) and reperfusion (90 minutes) group. The femoral artery vascular reactivity was studied in vitro with the aid of an eight "organ chambers'' setup, where segments from 4 to 5 mm, with and without endothelium, were suspended and connected to force transducers. The fundamental data of this study were as follows: (1) Ischemia caused by 120 minutes of infrarenal aortic clamping did not cause femoral artery endothelium dysfunction. (2) Ischemia caused by 90 minutes of clamping followed by 60 minutes of reperfusion also did not cause endothelium dysfunction, with an observed tendency to signal transduction impairment (studied by the sodium fluoride dose response curves). (3) Ischemia caused by 120 minutes of clamping followed by 90 minutes of reperfusion caused endothelium dysfunction, observed by the femoral artery impaired capacity of the endothelium-dependent NO release evoked by acetylcholine, adenosine diphosphate, and sodium fluoride. The present pharmacologic in vitro observations are concordant with the evidence that the NO-release impairment, caused by inferior canine hindlimb ischemia followed by reperfusion, is a consequence of endothelium cell membrane receptors, and G-proteins signal transduction dysfunction.

Animals↗
PubMed1995

Endothelium-dependent responses in hypertension.

The endothelium controls the tone of the underlying vascular smooth muscle by releasing relaxing factors. These include prostacyclin, nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF). In certain types of hypertension, endothelium-dependent relaxations are curtailed, because of a reduced production and/or action of endothelium-derived NO and EDHF. In the spontaneously hypertensive rat, endothelium-dependent relaxations are reduced, because of the endothelium-dependent production of vasoconstrictor prostanoids (endoperoxides and, in some cases, thromboxane A2). These prostanoids may be produced in the vascular smooth muscle cells rather than in the endothelium. The endothelial dysfunction observed in hypertensive blood vessels is likely to be a consequence rather than a cause of the disease process.

Animals↗
PubMed1991

Endothelium-dependent contraction and relaxation of the human and canine internal mammary artery: studies on bypass graft vasospasm.

The internal mammary artery (IMA) is the preferred conduit for coronary artery bypass graft because of superior late patency. However, IMA vasospasm may contribute to myocardial ischemia and early postoperative morbidity. To investigate mechanisms of vasospasm, we compared the reactivity of human and canine IMA segments in vitro to agonists known to release endothelium-derived contracting factor and endothelium-derived relaxing factor. Rings (4 mm in length) of human and canine IMA were studied in organ chambers. Human and canine vascular smooth muscle exhibited comparable contraction to norepinephrine (maximum = 7.55 +/- 0.63 gm and 6.4 +/- 0.90 gm, respectively) and relaxation to sodium nitroprusside. Human and canine IMAs exhibited comparable endothelium-derived relaxing factor-mediated relaxations to acetylcholine (human) and methacholine (canine). Human and canine IMA also exhibited comparable endothelium-dependent contraction to hypoxia (to 173.3% +/- 8.1% and 178.9% +/- 16.0% of initial prehypoxic tension; means +/- SEM; n = 12). Endothelium-dependent contraction to hypoxia in human and canine IMA could be attenuated by NG-monomethyl-L-arginine (10(-6) mol/L), a competitive inhibitor of L-arginine metabolism (n = 9 and n = 10 for human and canine; p less than 0.05). These studies establish that the canine is an appropriate model for study of human IMA vascular reactivity and that hypoxia can induce the release of an L-arginine-dependent, endothelium-derived contracting factor in the human and canine IMA. In vivo, the release of endothelium-derived contracting factor in response to hypoxemia may be cause of IMA vasospasm.

Acetylcholine↗
PubMed1989

Endothelium-dependent relaxing factors do not affect the smooth muscle of portal-mesenteric veins.

Experiments were designed to analyze the difference in endothelium-dependent responsiveness to acetylcholine between arteries and veins. The effect of endothelium-derived relaxing factor(s) released from femoral arteries of the dog was compared on the coronary artery of the dog, the aorta of the rat, and portal-mesenteric veins of both species. Endothelium-derived relaxing factor(s) released by canine femoral arteries induced comparable relaxation of the canine coronary artery and the aorta of the rat. However, neither the canine nor the rat portal vein relaxed when exposed to endothelium-derived relaxing factor(s) released by the femoral arterial segments. Endothelium-derived relaxing factor(s) did not affect the action potentials and the spontaneous activity of the rat portal vein. Sodium nitroprusside induced complete relaxation of the canine coronary artery but failed to abolish the spontaneously evoked contractions of the portal veins. These experiments suggest that the longitudinal smooth muscle of portal veins is insensitive to endothelium-derived relaxing factor(s), presumably because of a different sensitivity of guanylate cyclase. Endothelium-derived relaxing factor does not possess calcium-entry blocking properties.

Acetylcholine↗
PubMed1997

Characterization of endothelium-derived relaxing factors released by bradykinin in human resistance arteries.

1. Relaxing factors released by the endothelium and their relative contribution to the endothelium-dependent relaxation produced by bradykinin (BK) in comparison with different vasodilator agents were investigated in human omental resistance arteries. 2. BK produced an endothelium-dependent relaxation of arteries pre-contracted with the thromboxane A2 agonist, U46619. The B2 receptor antagonist, Hoe 140 (0.1, 1 and 10 microM), produced a parallel shift to the right of the concentration-response curve to BK with a pA2 of 7.75. 3. Neither the cyclo-oxygenase inhibitor, indomethacin (10 microM) alone, the nitric oxide synthase inhibitor, N omega-nitro-L-arginine methyl ester (L-NAME, 300 microM) alone, the nitric oxide scavenger, oxyhaemoglobin (Hb, 10 microM) alone, nor the combination of L-NAME plus Hb affected the concentration-response curve to BK. Conversely, the combination of indomethacin with either L-NAME or Hb attenuated but did not abolish the BK-induced relaxation. By contrast, the relaxations produced by the Ca2+ ionophore, calcimycin (A23187), and by the inhibitor of sarcoplasmic reticulum Ca(2+)-ATPase, thapsigargin (THAPS), were abolished in the presence of indomethacin plus L-NAME. Also, the presence of indomethacin plus L-NAME produced contraction of arteries with functional endothelium. 4. The indomethacin plus L-NAME resistant component of BK relaxation was abolished in physiological solution (PSS) containing 40 mM KCl and vice versa. However, in the presence of KCl 40 mM, indomethacin plus L-NAME did not affect the nitric oxide donor, S-N-acetylpenicillamine-induced relaxation. 5. The indomethacin plus L-NAME resistant component of the relaxation to BK was significantly attenuated by the K+ channel blocker tetrabutylammonium (TBA, 1 mM). However, it was not affected by other K+ channel blockers such as apamin (10 microM), 4-aminopyridine (100 microM), glibenclamide (10 microM), tetraethylammonium (10 mM) and charybdotoxin (50 nM). 6. In the presence of indomethacin plus L-NAME, the relaxation produced by BK was not affected by the phospholipase A2 inhibitor, quinacrine (10 microM) or by the inhibitor of cytochrome P450, SKF 525a (10 microM). Another cytochrome P450 inhibitor, clotrimazole (10 microM) which also inhibits K+ channels, inhibited the relaxation to BK. 7. These results show that BK induces endothelium-dependent relaxation in human small omental arteries via multiple mechanisms involving nitric oxide, cyclo-oxygenase derived prostanoid(s) and another factor (probably an endothelium-derived hyperpolarizing factor). They indicate that nitric oxide and cyclo-oxygenase derivative(s) can substitute for each other in producing relaxation and that the third component is not a metabolite of arachidonic acid, formed through the cytochrome P-450 pathway, in these arteries.

Arteries↗
PubMed2005

Investigation of vascular responses in endothelial nitric oxide synthase/cyclooxygenase-1 double-knockout mice: key role for endothelium-derived hyperpolarizing factor in the regulation of blood pressure in vivo.

BACKGROUND: Endothelium-dependent dilatation is mediated by 3 principal vasodilators: nitric oxide (NO), prostacyclin (PGI2), and endothelium-derived hyperpolarizing factor (EDHF). To determine the relative contribution of these factors in endothelium-dependent relaxation, we have generated mice in which the enzymes required for endothelial NO and PGI2 production, endothelial NO synthase (eNOS) and cyclooxygenase-1 (COX-1), respectively, have been disrupted (eNOS-/- and COX-1-/- mice). METHODS AND RESULTS: In female mice, the absence of eNOS and COX-1 had no effect on mean arterial blood pressure (BP), whereas BP was significantly elevated in eNOS-/-/COX-1-/- males compared with wild-type controls. Additionally, endothelium-dependent relaxation remained intact in the resistance vessels of female mice and was associated with vascular smooth muscle hyperpolarization; however, these responses were profoundly suppressed in arteries of male eNOS-/-/COX-1-/- animals. Similarly, the endothelium-dependent vasodilator bradykinin produced dose-dependent hypotension in female eNOS-/-/COX-1-/- animals in vivo but had no effect on BP in male mice. CONCLUSIONS: These studies indicate that EDHF is the predominant endothelium-derived relaxing factor in female mice, whereas NO and PGI2 are the predominant mediators in male mice. Moreover, the gender-specific prevalence of EDHF appears to underlie the protection of female eNOS-/-/COX-1-/- mice against hypertension.

6-Ketoprostaglandin F1 alpha↗
PubMed2005

14,15-epoxyeicosatrienoic acid represents a transferable endothelium-dependent relaxing factor in bovine coronary arteries.

Bradykinin causes arterial relaxation and hyperpolarization, which is mediated by a transferable endothelium-derived hyperpolarizing factor (EDHF). In coronary arteries, epoxyeicosatrienoic acids (EETs) are involved in the EDHF response. However, the role of EETs as transferable mediators of EDHF-dependent relaxation remains poorly defined. Two small bovine coronary arteries were cannulated and perfused in tandem in the presence of the nitric oxide synthase inhibitor, nitro-L-arginine (30 micromol/L), and the cyclooxygenase inhibitor, indomethacin (10 micromol/L). Luminal perfusate from donor arteries with intact endothelium perfused endothelium-denuded detector arteries. Detector arteries were constricted with U46619 and diameters were monitored. Bradykinin (10 nmol/L) added to detector arteries did not induce dilation (5+/-2%), whereas bradykinin addition to donor arteries dilated detector arteries by 26.5+/-7% (P<0.05). These dilations were blocked by donor artery endothelium removal and detector artery treatment with the EET-selective antagonist, 14,15-epoxyeicosa-5(Z)-monoenoic acid (14,15-EEZE; 10 micromol/L, -5+/-6%) but not 14,15-EEZE treatment of donor arteries (20+/-5%). 14,15-EET (0.1 to 10 micromol/L) added to detector arteries induced maximal dilations of 82+/-5% that were inhibited 50% by detector artery treatment with 14,15-EEZE (32+/-12%) but not donor artery treatment with 14,15-EEZE. Liquid chromatography-electrospray ionization mass spectrometry analysis verified the presence of 14,15-EET in the perfusate from an endothelium-intact but not denuded artery. These results show that bradykinin stimulates donor artery 14,15-EET release that dilates detector arteries. 14,15-EEZE blocked the donor artery, endothelium-dependent, bradykinin-induced relaxations, and attenuated relaxations to 14,15-EET. These results suggest that EETs are transferable EDHFs in coronary arteries.

8,11,14-Eicosatrienoic Acid↗
PubMed2007

Variable adhesion of different red blood cell products to activated vascular endothelium under flow conditions.

Red blood cells (RBCs) that have been stored prior to transfusion show increased adherence to vascular endothelium in vitro, which suggests a potential for stored blood transfusion to impede blood flow in some patients. Transfusion is often required in patients with sepsis or inflammation; however, whether activation of endothelium affects stored RBC-endothelial cell (EC) interactions is unknown. We investigated whether storage time and leukocyte content of RBC products influences the adhesion of RBCs to activated ECs. RBCs from nonleukocyte-reduced (S-RBCs), buffy-coat-poor (BCP-RBCs), and leukocyte-filtered (LF-RBCs) products and cultured EC layers were pretreated with endotoxin, tumor necrosis factor-alpha (TNF-alpha), or medium alone prior to perfusion of the RBCs across the EC layer in a continuous flow microchamber. After a single day of RBC storage, the number of adherent RBCs was increased in the endotoxin and TNF-alpha pretreated groups compared to the unactivated-control group. These differences were statistically significant for S-RBCs and LF-RBC products (P < 0.05). In contrast, there was no significant difference in RBC adherence to activated and unactivated endothelium at other time-points of RBC product storage. The strength of adhesion of stored RBCs from S-RBC products to activated ECs was not altered following treatment; however, endotoxin significantly increased the adhesive strength of LF-RBCs to endothelium. These results demonstrate that while fresh RBCs show increased adhesion to activated endothelium, storage of RBCs did not promote increased adhesion to activated endothelium. However, inflammatory conditions promote stronger adhesion of stored RBCs to ECs, which may contribute to impaired tissue perfusion in some transfusion recipients.

Blood Component Removal↗
PubMed1995

Significance of endothelium in the fine-needle aspiration biopsy diagnosis of hepatocellular carcinoma.

We reviewed fine-needle aspiration biopsies (FNAB) of hepatocellular carcinoma (HCC) (n = 35), benign hepatic processes (n = 35), cholangiocarcinoma (CC) (n = 6), and metastatic tumors (n = 100) to evaluate the significance of endothelium present either peripherally-wrapping around groups of cells, (peripheral endothelium (PE)), or transgressing sheets of cells (transgressing endothelium (TE)), in distinguishing these lesions. These patterns were assessed as absent, focal, or prominent. Thirty-three of 35 (94%) HCCs contained either focal or prominent PE or TE, compared to only 3 of 35 (9%) benign hepatocytic lesions. Only one benign lesion contained a prominent endothelial component (TE only). Two cases of HCC failed to contain endothelium, one fibrolamellar variant and one well-differentiated HCC. These differences were statistically significant (P < 10(-5), sensitivity 94%, specificity 91%, and positive predictive value [PPV] 92%). Neither pattern of endothelium was present in any CC or metastatic tumor. These differences were also statistically significant (P < 10(-5), sensitivity 94%, and specificity and PVP 100%). We conclude that the presence of endothelium, at least focally in either one or both distinctive patterns, is highly sensitive and specific for HCC and aides in distinguishing it from benign hepatocytic lesions, CC, and metastases.

Adenoma, Bile Duct↗
PubMed1984

Influence of migratory blood cells on the attachment of tumor cells to vascular endothelium.

The purpose of this study was to determine whether the presence of migratory blood cells in association with tumor emboli had the capacity to alter the attachment of tumor cells to vascular endothelium. Highly metastatic RT7-4bs rat hepatocarcinoma cells were labelled with [125I]UdR before being allowed to form mixed cellular spheroids incorporating resident peritoneal macrophages, activated peritoneal macrophages, polymorphonuclear leukocytes, splenic T lymphocytes, or splenic B lymphocytes derived from both normal and tumor-bearing animals. The presence of polymorphonuclear leukocytes or activated macrophages led to a considerable increase in the number of tumor cells attaching to endothelial cell monolayers in vitro. The presence of T or B lymphocytes from either normal or tumor-bearing rats was without effect on tumor attachment to endothelium. Increased tumor cell retention in the lungs was evident for mixed spheroids containing tumor cells and polymorphonuclear leukocytes compared to homotypic tumor spheroids composed of tumor cells alone. Furthermore, preinjection of polymorphonuclear leukocytes intravascularly or inoculation of tumor cells as heterotypic spheroids containing polymorphonuclear leukocytes increased lung colony formation over that obtained after inoculation of tumor cells alone. Several simple sugars were tested for their ability to block tumor cell, polymorphonuclear leukocyte or activated macrophage binding to endothelium in vitro. The results indicate that the glycosylated cell surface components mediating tumor cell attachment to endothelium are not identical with those mediating attachment of either polymorphonuclear leukocytes or activated macrophages. Medium conditioned during mixed spheroid formation was without effect on tumor cell attachment to endothelium. We conclude that the presence of some, but not all classes of leukocytes can modulate tumor cell attachment to vascular endothelium, an effect most likely mediated by a mechanism involving direct contact between the leukocytes and the endothelial cell monolayer.

Animals↗
PubMed1995

The increased expression of adhesion molecules ICAM-3, E- and P-selectins on breast cancer endothelium.

Sequential interaction of neoplastic cells with the endothelium of tumour neovasculature is believed to be a significant step in tumour metastasis. Increasing evidence suggests that inducible endothelial adhesion molecules are intimately involved in this process. An immunohistochemical approach was used to examine the expression of adhesion molecules in 14 normal controls and a series of 64 invasive breast carcinomas. Endothelium in normal breast showed constitutive expression of PECAM (100 per cent), ICAM-2 (100 per cent), and P-selectin (64 per cent); variable and focal expression of ICAM-1 (71 per cent); and only weak staining for E-selectin (21 per cent). No ICAM-3 or VCAM-1 expression was observed. Similarly to normal breast endothelium, widespread and intense immunoreactivity on the endothelium of tumour-associated vessels was seen for PECAM (100 per cent), ICAM-1 (69 per cent), and ICAM-2 (95 per cent). In contrast to normal tissues, E- and P-selectins showed increased intensity of staining (52 and 67 per cent of cases, respectively) and expression of E- and P-selectins was more prominent at the tumour periphery. ICAM-3 expression was increased on tumour endothelium (15 per cent of cases), but in common with VCAM-1 (10 per cent) expression was focal. A previously unreported finding was the immunoreactivity of the neoplastic epithelial cells for the non-epithelial lineage markers ICAM-1 (34 per cent), ICAM-3 (10.9 per cent), PECAM (1.6 per cent), and E- and P-selectins (7 and 37 per cent of cases, respectively). These findings show that tumour endothelium displays significant heterogeneity and can assume a pro-inflammatory phenotype, probably as a result of cytokine stimulation. Upregulation of adhesion molecules might contribute to changes in invasive phenotype by promoting endothelial cell adhesion and angiogenesis, as well as forming a substratum for tumour cells to assemble and attract macrophages.

Adult↗
PubMed2003

Endothelium-dependent contraction of rat thoracic aorta induced by gallic acid.

The vascular effect of a component of hydrolysable tannins, gallic acid, was examined in isolated rat thoracic aorta. Gallic acid exerted a contractile effect on the phenylephrine- or prostaglandin F(2/alpha)-precontracted endothelium-intact arteries. In endothelium-denuded arteries, the contractile response to-gallic acid was absent. Pretreatment with N(G)-nitro-L-arginine methyl ester (30 microM) abolished the gallic acid-induced contraction. Pretreatment with indomethacin (10 microM) or BQ610 (100 nM) had no observed effect. Pretreatment with gallic acid (1-10 microM) significantly attenuated the relaxation induced by acetylcholine, and that with 10 microM gallic acid also reduced the potency of sodium nitroprusside in the relaxation, without a reduction in efficacy, in endothelium-denuded arteries. These findings indicate that gallic acid induced endothelium-dependent contraction and strongly inhibited the endothelium-dependent relaxation rather than the endothelium-independent relaxation, probably through inhibition of endothelial nitric oxide (NO) production. Since NO plays an important role in vasodilative regulation and inflammatory disorders, these findings may also indicate that gallic acid interferes with the inflammatory responses.

Acetylcholine↗
PubMed2002

Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in human mesenteric arteries.

The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several vasodilating factors, including prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor (EDHF). We have recently identified that endothelium-derived hydrogen peroxide (H(2)O(2)) is an EDHF in mice. The present study was designed to examine whether this is also the case in humans. Bradykinin elicited endothelium-dependent relaxations and hyperpolarizations in the presence of indomethacin and N(omega)-nitro-l-arginine, which thus were attributed to EDHF, in human mesenteric arteries. The EDHF-mediated relaxations were significantly inhibited by catalase, an enzyme that specifically decomposes H(2)O(2), whereas catalase did not affect endothelium-independent hyperpolarizations to levcromakalim. Exogenous H(2)O(2) elicited relaxations and hyperpolarizations in endothelium-stripped arteries. Gap junction inhibitor 18alpha-glycyrrhetinic acid partially inhibited, whereas inhibitors of cytochrome P450 did not affect the EDHF-mediated relaxations. These results indicate that H(2)O(2) is also a primary EDHF in human mesenteric arteries with some contribution of gap junctions.

Aged↗
PubMed1997

Role of oxidative metabolism on endothelium-dependent vascular relaxation of isolated vessels.

The obligatory role of endothelium in mediating vasodilator response to numerous humoral agents has been definitely accepted. However, the chemical identity of endothelium-derived relaxing factor(s) (EDRF) and the mechanisms underlying its synthesis and release remain unclear. Much evidence suggests a compartmentalization of ATP into cells, such that ATP derived from glycolysis or from oxidative metabolism is used for different cellular functions. To investigate which energy source (i.e. oxidative v glycolytic metabolism) is preferentially used for the biosynthesis and/or release of EDRF, rings of rabbit thoracic aorta were studied in organ chambers. After preconstriction with PGF2 alpha, inhibition of glycolysis with either iodoacetate (300 microM) (n = 6) or 2-deoxyglucose (20 mM) (n = 6) did not affect concentration-response curve to the endothelium-dependent agent acetylcholine. In contrast, inhibition of oxidative metabolism with either 1 mM amytal or 5 microM rotenone markedly impaired relaxation to acetylcholine. In fact, maximal relaxation was 75 +/- 5% in control rings (n = 6), and 42 +/- 7% (P < 0.01) in amytal-treated rings (n = 6), whereas rotenone converted acetylcholine relaxation into constriction (n = 6; P < 0.001). The effect of amytal on endothelium-dependent relaxation was reversible, suggesting that endothelial cells were not damaged by the inhibitor. Amytal also markedly reduced endothelium-mediated relaxation to ADP (37 +/- 6%; P < 0.05; n = 5), as well as to the calcium ionophore A23187. Neither mitochondrial inhibitor affected relaxation to nitroglycerin, an endothelium-independent agent. Finally, amytal did not affect relaxation to S-nitrosocysteine (a recently proposed EDRF) (n = 5), suggesting that the effects on acetylcholine and ADP responses were not due to non-specific interferences with EDRF once released from endothelial cells. In conclusion, our data demonstrate that the active process of biosynthesis and/or release of EDRF requires energy derived mainly from mitochondrial oxidative metabolism.

Acetylcholine↗
PubMed2001

Measurement of membrane potential and intracellular Ca(2+) of arteriolar endothelium and smooth muscle in vivo.

We have developed an intensity analysis technique for fluorescence microscopy that allows us to measure, in real time, the diameter and the membrane potential or intracellular calcium ([Ca(2+)]i) of in vivo arteriolar endothelium or smooth muscle. Cheek pouch arterioles of anesthetized hamsters were luminally or abluminally labeled with Di-8-ANEPPS, a voltage-sensitive dye, or Fura PE3, a calcium indicator. The peak fluorescence intensities of the images were used to locate the endothelium or smooth muscle. The changes in membrane potential or [Ca(2+)]i were determined based on the ratiometric analysis of fluorescence intensity of the endothelium or smooth muscle. Membrane depolarization of the smooth muscle using KCl caused a decrease in the ratio of emission, 620 nm/560 nm ( approximately 6 mV/% ratio). The ratio of excitation, 340 nm/380 nm, increased with increasing free Ca(2+). Methacholine, a muscarinic receptor agonist, caused arteriolar dilation (12.2 +/- 0.9 &microm). It produced hyperpolarization of the endothelium and smooth muscle (2.8 +/- 0.6% and 2.3 +/- 0.3% in ratio). Methacholine also induced an increase in [Ca(2+)]i (11.0 +/- 1.1% in ratio) of the endothelium. In contrast, methacholine caused a biphasic change in [Ca(2+)]i of the smooth muscle, a rapid reduction (-3.4 +/- 0.2% in ratio) followed by a prolonged increase (2.4 +/- 0.2% in ratio). These results demonstrate that the peak intensity analysis can be used to determine in real time the changes in membrane potential or [Ca(2+)]i of in vivo endothelium or smooth muscle.

Animals↗
PubMed1997

Characterization of a peptide endothelium-derived constricting factor EDCF.

Endothelium regulates vascular tone by the release of dilator and constrictor mediators. Among the latter, besides endothelin, an 'endothelium derived constricting factor' EDCF sensitive to cyclooxygenase-inhibitors has been described. The aim of this study was to clarify the nature of this EDCF. Eluate from porcine aortic segments or supernatants (crude extracts) of porcine aortic segments were each tested for vascular effects in a bioassay system consisting of two endothelium-denuded acceptor vessels (rabbit abdominal aorta) before or after treatment with trypsin. The donor vessels were incubated with physiological saline solution with or without treatment with cycloheximide, quinacrine or indomethacine. Ultrafiltrates and fractions of a gelfiltration of the supernatants were also tested and compared with SDS-PAGE of these extracts. Finally, porcine aortic endothelial cells (PAEC) were cultured and the supernatant compared with that of the native aortae. A vasoconstrictive factor was released from the luminal surface of the porcine aortic segments, which if infused into the rabbit aortas induced two succeeding vasoconstrictions of 15-20 min duration each (the first 20 min after the first of extract-infusion, the second after 50 min) reaching 7% amplitude of a 0.2 mumol 1(-1) norepinephrine-induced constriction. These constrictions were enhanced if the crude extract of the porcine aortae was concentrated. This constricting factor was a protein with an approximative molecular weight of 9.000 Da. The release of this factor was insensitive to cycloheximide pretreatment indicating no de novo synthesis. However, the release of the factor could be markedly (50%) depressed by pretreatment with either quinacrine or indomethacine. The factor was not released from cultured PAEC. From these results, we conclude, that besides endothelin, endothelium luminally can release another endothelium-derived constricting factor named EDCF, a peptide with a molecular weight of 9.000 Da, which is not identical to endothelium and can induce long lasting vasoconstrictions. The release or synthesis of that EDCF seems to depend on cyclooxygenase and phospholipase A2 activity. We, thus, propose the name PLA2-sensitive EDCF for that factor.

Analysis of Variance↗
PubMed1991

Endothelium-dependent control of vascular tone: effects of age, hypertension and lipids.

As a source of several vasoactive factors, the endothelium takes part in the regulation of vascular tone. The most important endothelium-derived vasoactive substances are nitric oxide, prostacyclin, endothelin-1 and contracting factors requiring the activity of cyclooxygenase. The endothelium is an obvious target organ of cardiovascular risk factors. Accordingly, functional alterations do occur with aging, hypertension, and lipids. All three conditions are associated with a decreased basal and stimulated release of endothelium-derived nitric oxide. On the other hand, the release of endothelin-1 appears to increase with age, while the sensitivity to the peptide markedly decreases under the same conditions. In the spontaneously hypertensive rat, acetylcholine and stretch evoke the release of cyclooxygenase-dependent endothelium-derived contracting factor, most likely prostaglandin H2. The sensitivity and circulating levels of endothelin-1, on the other hand, are reduced in this experimental model of hypertension. In the porcine coronary circulation, oxidized low-density lipoproteins selectively reduce endothelium-dependent relaxations to aggregating platelets, serotonin, and thrombin which are mediated by nitric oxide. The alterations of endothelial function occurring with aging, hypertension, and hyperlipidemia may have important clinical implications for the pathogenesis of cardiovascular disease.

Aging↗
PubMed1989

Cultured brain endothelium inhibits the cytocidal action of natural killer cells on glioma.

The killing of GL26 and YAC-1 cells by natural killer cells (NKC) is reduced in the presence of a monolayer of endothelial cells. This reduction in cytotoxicity correlates with the degree of adhesion between the tumor cells and the endothelial monolayers. The cytotoxicity of NKC toward glioma was 10% when carried out on plastic, but a monolayer of endothelium derived from brain inhibited the cytotoxicity by about 90%. Endothelium from thoracic duct and lung also inhibited cytotoxicity by about 90%, endothelium from aorta inhibited by 55% and that from ovary by only 45%. Cytotoxicity of NKC toward YAC-1 (a control NK target) was 40% on plastic, but a monolayer of endothelium from thoracic duct inhibited the cytotoxicity by 75%. Endothelium from brain and lung inhibited cytotoxicity by about 60%, aorta by 50%, and ovary by 40%. Interactions between tumor cells and the host-organ microvascular endothelium appear to protect neoplastic cells from natural surveillance mechanisms and may play a role in the formation of metastatic tumor deposits.

Animals↗