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PubMed1996

Antisense evidence for two functionally active forms of nitric oxide synthase in brain microvascular endothelium.

Other workers have identified two constitutive forms of NOS in endothelial cells: endothelial or eNOS and neuronal or nNOS. The present study tests the functional significance of these NOS in brain surface arterioles of mice. Antisense oligodeoxynucleotides (ODN) were injected into the cerebral ventricles. Anti eNOS and anti nNOS were tested separately and in combination. Each antisense reduced the dilation produced by topical acetylcholine (ACh) or by tetrahydrobiopterin (THBP). These are endothelium dependent, NOS dependent dilators, with the THBP being a cofactor for NOS. The endothelium derived mediator actually causing the dilation is EDRF(ACh). When both antisenses were given together there was an additive effect which approached 100% inhibition. Neither sense nor mismatched (scrambled) ODN inhibited either ACh or THBP. Moreover, anti eNOS did not inhibit dilation by bradykinin (endothelium dependent but not NOS dependent) or by sodium nitroprusside (endothelium independent). The data strongly support the conclusion that both eNOS and nNOS are functionally important in the endothelium of mouse pial arterioles. Each isoform of NOS appears to contribute significantly to the synthesis of basally released (THBP triggered) and agonist (ACh) released EDRFACh.

Analysis of Variance↗
PubMed1998

Dirofilaria immitis: heartworm infection converts histamine-induced constriction to endothelium-dependent relaxation in canine pulmonary artery.

Heartworm (Dirofilaria immitis) infection alters the behavior of vascular endothelial cells in vivo and in vitro, with the potential, therefore, to influence vascular function. Histamine, an autocoid implicated in the pathogenesis of parasitic and inflammatory diseases, is vasoactive, and causes endothelium-dependent relaxation in some vascular beds. Experiments were designed to determine if histamine is an endothelium-dependent vasodilator in in vitro rings of canine pulmonary artery from heartworm and control dogs; to elucidate the mechanisms involved in histamine vasoactivity; and to measure circulating levels of histamine. Dose-response relationships to histamine were done in rings of canine pulmonary artery from heartworm and control dogs, in the presence and absence of endothelial cells, the H1 receptor blocker tripelennamine, or the H2 receptor blocker cimetidine. Histamine caused a dose-dependent constriction in control, that was not influenced by endothelial cell removal. However, histamine caused an endothelium-dependent relaxation in heartworm pulmonary artery that was converted to constriction by endothelial cell removal. In heartworm, histamine relaxation was mediated by H2 receptors, but did not appear to involve nitric oxide or cyclooxygenase products. While diseases cause depression of endothelium-dependent relaxation, this is the first report of a disease that changes a constriction response to an endothelium-dependent relaxation.

Animals↗
PubMed1993

The role of the endothelium in systemic vasculitis.

The critical role played by the vascular endothelium in the development of vasculitic disease will be discussed within this article, attention being focused on the pathogenesis of the primary vasculitides, particularly Wegener's granulomatosis, microscopic polyarteritis and Kawasaki disease. Under normal circumstances the endothelium constitutes a barrier to the efflux of plasma proteins into the extracellular tissues, serves to maintain an anti-coagulant environment and forms a platform upon which many important biological processes take place. Alteration of the balance of these functions by inflammatory mediators and cytokines leads to the formation of a pro-coagulant environment, fluid leakage and increased adhesivity of the endothelium for neutrophils and lymphocytes. Both neutrophils and lymphocytes have the capacity to damage the endothelium directly, by the secretion of oxygen radicals, enzymes and other cytotoxic molecules, or indirectly by the secretion of cytokines which may alter the biological properties of endothelial cells, a process called endothelial activation. The role played by antibodies to the endothelium and to neutrophil cytoplasm components in mediating vascular injury in systemic vasculitis is also discussed and, finally, injury precipitated by components of the coagulation/thrombotic system.

Arteritis↗
PubMed1996

Endothelium-dependent responses in congestive heart failure.

The endothelium is a major regulator of vascular tone because it releases vasoactive substances including: endothelium-derived relaxing factor (nitric oxide/EDRF), endothelium-derived hyperpolarizing factor (EDHF), prostacyclin, endothelin and endothelium-derived contracting factors (EDCFs). Three of these factors, nitric oxide, endothelin and a cyclooxygenase-dependent EDCF may play a role in congestive heart failure. A number of experimental and clinical studies describe impaired endothelium-dependent vasodilatations and increased plasma concentration of endothelin in congestive heart failure. The decrease of cardiac output, that results in a reduced shear stress on the endothelial cells and systemic endocrine compensatory mechanisms such as increased production of angiotensin-converting enzyme (leading to a greater breakdown of kinins) can modulate the release of nitric oxide and endothelin. It is unclear to which extent these modulations initiate, maintain, and/or compensate for the pathological process.

Animals↗
PubMed1997

Age-dependent changes in the effects of endocardial endothelium on the contractile characteristics of its adjacent myocardium in rats.

Cardiac contractility and the ability of myocardium to respond to various stimuli have been shown to be age-related. Endocardial endothelium has been shown to modulate the performance of its adjacent myocardium, and it has been proven that these changes are reversible by increasing extracellular calcium. This study was designed to evaluate whether the effects of endocardial endothelium and their modifications with changing extracellular calcium were age-dependent. Experiments were carried out on left ventricular papillary muscles isolated from male Wistar rats belonging to three different age groups 7 weeks, 4 months, and 9 months old. Extracellular calcium concentration (0.7 to 5 mM) curves were conducted in papillary muscles with intact endocardial endothelium (+ EE) and after its removal (- EE) with Triton X-100. At a low extracellular calcium concentration (0.7 mM), total tension (TT), maximum rate of tension development (+ dT/dt), time to peak tension (TTPT), and time to half tension decline from maximum tension (RT1/2) increased with increasing age (P < 0.01). Increasing extracellular calcium concentration eliminated age-related differences in TT and RT1/2 did not affect TTPT and caused + dT/dt to increase to greater levels in 7-week-old as compared to 4-month-old myocardium. Endocardial endothelial removal (-EE) had a greater effect on contractile indices in younger rats. Increasing extracellular calcium concentration eliminated EE-mediated changes in contractile indices regardless of age. Thus, increasing extracellular calcium concentration had a greater effect in younger rats and after -EE. Increasing extracellular calcium from 0.7 to 2.5 mM increased total tension in 7-week-olds, between 56% +EE and 131% -EE (P < 0.01): in 4-month-olds, from 29% +EE to 57% -EE (P < 0.01): and in 9-month-olds. from 13% +EE to 23% -EE (P = 0.08). These results indicate that the contractile effects of endocardial endothelium are both age- and calcium-dependent, with responsiveness to endocardial endothelium decreasing with age. Myocardial contractile characteristics also vary with age and these differences are only partially reversible with increasing extracellular calcium concentration.

Age Factors↗
PubMed1994

Delayed recovery of endothelium-dependent vasodilation in regenerating arterioles of skeletal muscle autografts.

This study investigated the responses of regenerating arterioles in grafted skeletal muscle to the endothelium-dependent dilator acetylcholine (ACh); the substrate for endothelium-derived relaxing factor (EDRF), L-arginine (L-Arg); and sodium nitroprusside (SNP). Additionally, responses of graft arterioles to the endothelium-independent substances adenosine (Ado) and norepinephrine (NE) were measured. The retractor muscle of hamsters was removed, placed in a myotoxic solution, and grafted into its original site. The graft revascularized spontaneously by sprouting of vessels in surrounding tissue. Quantification of changes in arteriolar luminal diameter was accomplished using in vivo video microscopy at 30, 45, and 60 days postgrafting. In 30-day grafts, there was little or no response to topically applied ACh or L-Arg. By 45 days, arteriole response to 10(-6), 10(-5), and 10(-4) M ACh and 10(-4) L-Arg was 0, 4, 20, and 17% of the control response, respectively. SNP (10(-6)-10(-4) M) produced approximately 50% of the control response at both 30 and 45 days. By 60 days the response of graft arterioles to ACh, L-Arg, and SNP was not different from controls. Arteriolar response in 30-day grafts to Ado (10(-6)-10(-4) M) was significantly attenuated, but was not different from control by 45 days. Responsiveness of arterioles to NE had recovered to control levels by 30 days postgrafting. These data indicate that the restoration of endothelium-dependent regulation of arteriolar dilation lags behind endothelium-independent, receptor-mediated mechanisms. The diminished response of regenerating arterioles may be related to dysfunctions in both the synthetic pathway for EDRF and the guanylate cyclase/cGMP mechanism for vascular smooth muscle cell relaxation and/or flow-dependent mechanisms of blood flow regulation.

Acetylcholine↗
PubMed1999

Expression of immunoglobulin superfamily members on the lymphatic endothelium of inflamed human small intestine.

Previously, lymphatic endothelium of human tissue has been shown to express only platelet-endothelial cell adhesion molecule-1 (PECAM-1). In this study we examined the expression of immunoglobulin superfamily members on the lymphatic endothelium of human small intestine while in the presence of inflammatory cytokines. Lymphatic vessels were identified by using a cocktail of IgGs for desmoplakin I and II while the presence of inflammatory cytokines was determined by the expression of major histocompatibility complex (MHC) class II in the venules. As a result, lymphatic vessels in the tissue with venules expressing MHC class II expressed PECAM-1, intercellular adhesion molecule (ICAM)-1, ICAM-3, and vascular cell adhesion molecule-1 (VCAM-1). The expression of ICAM-3 and VCAM-1 was significantly stronger in lymphatic vessels than in blood vessels. The results suggest that inflamed lymphatic endothelium may allow more lymphocyte subpopulations to adhere to the endothelium than non-inflamed lymphatic endothelium, due to the expression of multiple adhesion molecules playing a role.

Aged↗
PubMed1993

Effects of melatonin on isolated pulmonary artery and vein: role of the vascular endothelium.

The influence of melatonin on tension of isolated pulmonary vascular smooth muscle rings was examined in these experiments. Melatonin caused a dose-dependent relaxation of precontracted (30 mM KCl) pulmonary artery and pulmonary vein. Removal of the endothelium did not alter the relaxant response to melatonin in pulmonary artery. In pulmonary artery with endothelium intact, preincubation with indomethacin, but not L-NG-monomethyl-L-arginine (L-NMMA) or deferoxamine, antagonized the relaxant response to melatonin. In pulmonary artery with endothelium removed, preincubation with deferoxamine, but not indomethacin, phorbol esters, or lithium chloride, antagonized the relaxant response to melatonin. In pulmonary vein, removal of the endothelium significantly increased the maximum relaxation attained in response to melatonin. In pulmonary vein with endothelium intact, preincubation with indomethacin, but not L-NMMA or deferoxamine, antagonized the relaxant response to melatonin. On the other hand, preincubation of de-endothelialized pulmonary vein with lithium chloride significantly increased the relaxation response to melatonin. These experiments demonstrate that both pulmonary artery and vein relax in response to melatonin and the mechanisms are apparently different.

Animals↗
PubMed2006

The vascular endothelium in hypertension.

The vascular endothelium plays a fundamental role in the basal and dynamic regulation of the circulation. Thus, it has a crucial role in the pathogenesis of hypertension. A spectrum of vasoactive substances is synthesised in the endothelium; of these, nitric oxide (NO), prostacyclin (PGI2) and endothelin (ET)-1 are the most important. There is a continuous basal release of NO determining the tone of peripheral blood vessels. Systemic inhibition of NO synthesis or scavenging of NO through oxidative stress causes an increase in arterial blood pressure. Also, the renin-angiotensin-aldosterone system has a major role in hypertension as it has a direct vasoconstrictor effect and important interactions with oxygen free radicals and NO. Prostacyclin, in contrast to NO, does not contribute to the maintenance of basal vascular tone of conduit arteries, but its effect on platelets is most important. ET acts as the natural counterpart to endothelium-derived NO and has an arterial blood pressure-raising effect in man. Anti-hypertensive therapy lowers blood pressure and may influence these different mediators, thus influencing endothelial function. In summary, due to its position between the blood pressure and smooth muscle cells responsible for peripheral resistance, the endothelium is thought to be both victim and offender in arterial hypertension. The delicate balance of endothelium-derived factors is disturbed in hypertension. Specific anti-hypertensive and anti-oxidant treatment is able to restore this balance.

Adrenergic beta-Antagonists↗
PubMed1993

Cerebral endothelium and astrocytes cooperate in supplying docosahexaenoic acid to neurons.

These findings confirm that astrocytes and cerebral endothelium, not neurons, are the cells primarily responsible for the desaturation of essential fatty acids in the brain. They suggest that cerebral endothelial cells can target omega-3 fatty acids for release from their basolateral surface and thus aid in the enrichment of omega-3 fatty acids observed in the brain. The studies further suggest that endothelium and astrocytes play an important supportive role in the brain by cooperating in the elongation and desaturation of omega-3 essential fatty acid precursors in the brain and in the transfer of DHA to neurons. In doing so, endothelium and astrocytes may contribute positively to the high level of fatty acid desaturation necessary for normal neuronal function. In composite, the present studies and previously published work support a model for supplying DHA to central nervous system neurons that could utilize either DHA or its omega-3 fatty acid precursors circulating in the blood (Figure 4). If preformed DHA were available, the cerebral endothelium would take it up and transfer it into the brain. An additional sequential pathway would utilize circulating linolenic acid or EPA. In this pathway cerebral endothelium would take up omega-3 fatty acid precursors and target them preferentially into the brain, performing some elongation and desaturation in the process. Astrocytes would subsequently complete the conversion of precursors to DHA, releasing it for uptake by neurons.

Animals↗
PubMed1991

Endothelium and blood flow mediated vasomotion in the conscious dog.

Numerous in vitro studies have demonstrated the important role of the vascular endothelium on the vasoactivity of vascular smooth muscle. Experimentation, particularly in conscious animals, is required to study the integrated role of endothelium in the regulation of vascular tone. This article reviews some of the evidence demonstrating endothelium mediated vasodilation and inhibition of vasoconstriction by the endothelium in the chronically instrumented conscious animal. Furthermore, a role for endothelial cells has been shown in the mechanism of blood flow-mediated vasodilation. Finally, the endothelium, through elaboration of constricting factors, e.g., endothelin, can also induce potent vasoconstriction. In the conscious animal endothelin elicits markedly differing degrees of vasoconstriction among the various regional vascular beds.

Animals↗
PubMed1990

Coronary endothelium-protective effects of defibrotide in ischaemia and reperfusion.

Defibrotide is known to enhance prostacyclin (PGI2) release from the vascular endothelium. We investigated the vasoactive effects of defibrotide in isolated rat hearts perfused at constant flow subjected to ischaemia and reperfusion. Defibrotide at 10 or 100 micrograms/ml did not exert any direct vasoactive effect on normal rats hearts. However, ischaemia and reperfusion resulted in an impaired vasodilation to acetylcholine, an endothelium-dependent vasodilator. In contrast, the vasodilator response to the endothelium-independent dilator, nitroglycerin, was unaffected. Defibrotide, at 10 or 100 micrograms/ml, markedly restored the vasodilation to acetylcholine 10 nmol/l to 1 mumol/l (P less than 0.01) without influencing the vasodilator response to nitroglycerin (2 to 200 micrograms/l). Haemoglobin (150 nmol/l) inhibited the dilation to acetylcholine in response to defibrotide. However, no evidence of PGI2 release was observed with acetylcholine-induced vasodilation in the presence or absence of defibrotide. Additionally, 10-100 micrograms/ml of defibrotide did not significantly decrease superoxide radicals generated by a xanthine-xanthine oxidase synthetic system under conditions in which superoxide dismutase was effective. Thus, defibrotide appears to exert an endothelium-protective effect preserving endothelium-derived relaxing factor (EDRF) without directly scavenging free signals.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1992

Cytokinetic studies on the aortic endothelium and limb bud vascularization in avian embryos.

Cytokinetic studies on the aortic endothelium using the BrdU/anti-BrdU-method were carried out on 2.5- to 6-day chick and quail embryos. The mitotic activity of the aortic endothelium is related temporally to the age of the avian embryo and spatially to the embryonic region where the aorta originates. The mitotic activity of the aortic endothelium decreases with increasing age of the embryos. In the limb buds, however, the mitotic rate of the aortic endothelial cells increases independently of the age of the embryo. This increase in the mitotic activity of the aortic endothelium at the appropriate levels coincides with the vascularization of the outgrowing limb buds. We concluded therefore that the aortic endothelium probably supplies endothelial cells for the formation of limb vessels at this stage. Thus our results suggest that angiogenesis (sprouting of capillaries from pre-existing vessels) takes place during limb vascularization in avian embryos. On the other hand, immunohistochemical studies with QH-1 or MB-1 antibody show, beside a capillary network in the central core of the wing bud, individual immunolabelled cells of mesenchymal character within the primarily avascular subectodermal region from the onset of vascularization onwards. We suggest that these cells have partly to be regarded as endothelial precursor cells, which have differentiated in situ from the local limb mesenchyme, and which will contribute to the developing vascular plexus. This means that not only angiogenesis, but also vasculogenesis (in situ from mesenchymal precursors differentiated endothelial cells) appears to be involved in limb vessel formation.

Animals↗
PubMedDate not supplied

NG-nitro-L-arginine (N5-[imino(nitroamino)methyl]-L-ornithine) impairs endothelium-dependent dilations by inhibiting cytosolic nitric oxide synthesis from L-arginine.

We studied the effects of the L-arginine analogue NG-nitro-arginine (L-NNA), in comparison with its D-isomer [D-NNA), on endothelium-dependent dilations of rabbit femoral arteries (RFA) and on the release of endothelium-derived relaxant factor (EDRF) from native and cultured endothelial cells. In addition, we examined the effects of L- and D-NNA on the L-arginine- and NADPH-dependent synthesis of nitric oxide (NO) in the cytosol of porcine aortic endothelial cells. L-NNA enhanced the noradrenaline-induced contraction of endothelium-intact, but not of endothelium-denuded segments of RFA, indicating an inhibition of basal EDRF release. L-NNA also inhibited significantly the endothelium-dependent dilations to acetylcholine (ACh). Both effects of L-NNA were attenuated by L-arginine. L-NNA rapidly inhibited the release of EDRF from cultured and native endothelial cells stimulated with thimerosal or ACh. L-NNA concentration-dependently and reversibly antagonized the L-arginine- and NADPH-dependent activation of a purified soluble guanylate cyclase (GC) by cytosol from freshly harvested porcine aortic endothelial cells, suggesting a direct competition between L-NNA and L-arginine at the level of endothelial NO-synthesis. D-NNA was ineffective in all instances. These results prove L-NNA to be a stereospecific inhibitor of the cytosolic NO formation from L-arginine in endothelial cells. Therefore, L-NNA will be a useful tool to elucidate the molecular mechanism of mammalian NO synthesis.

Acetylcholine↗
PubMed1987

Binding and endocytosis of heparin-gold conjugates by the fenestrated endothelium of the rat choriocapillaris.

Heparin-gold probes were used to localize regions of heparin binding on the luminal surface of the diaphragmed-fenestrated endothelium of the rat choriocapillaris. Structures of endothelial cells were unlabeled when rats were kept on ice and perfused with solutions at 4 degrees C. When the heparin-gold quantity was doubled, only a few heparin-gold particles marked some diaphragms spanning fenestrae, vesicles and channels, parajunctional regions of the plasmalemma, and coated pits. With solutions at 4 degrees C, but the animals kept at room temperature, all of these structures in the endothelial cells were labeled. This binding was not altered by the perfusion of low levels of unlabeled heparin, but was eliminated following high levels of unlabeled heparin, and by digestion with trypsin and pronase. At 37 degrees C, heparin was localized to the above structures and, in addition, was internalized into coated vesicles, endosomes, and multivesicular bodies, but not other types of lysosomes. Some particles were found in tubules adjacent to the Golgi stacks. Heparin-gold was also transported to the abluminal front of the endothelium by vesicles. A desulfated, non-anticoagulant, fraction of heparin bound to gold was localized to the endothelium in the same manner. These results demonstrate receptors for heparin on the surface of a fenestrated endothelium. Furthermore, they show the pathway of endocytosis and transport of heparin. The possible roles of heparin in the function of the endothelium is discussed.

Animals↗
PubMed1982

Permeability of the foetal capillary endothelium of the guinea-pig placenta to haem proteins of various molecular sizes.

Haem proteins of different molecular sizes were perfused into the foetal circulation of the guinea-pig placenta to study the permeability of the foetal endothelium. The smallest molecules tested, microperoxidase (ae 1.0 nm) and cytochrome C (ae 1.5 nm), readily penetrated the endothelium; tracer-reaction product was found in the subendothelial space of the capillaries. However, there was no uptake of these two tracers into the syncytiotrophoblast layer of the placenta. An intermediate-sized molecule, myoglobin (ae 1.7 nm) produced only a weak reaction product in the subendothelial space even when perfused at high concentration. The largest molecule tested, haemoglobin (ae 2.8 nm), did not penetrate the foetal endothelium at any of the concentrations employed. The foetal capillary endothelium thus provided a barrier to protein penetration from the foetal circulation, dependent on molecular size. There was evidence that the site of this barrier was located in the lateral intercellular spaces between the endothelial cells. The syncytiotrophoblast of this haemomonochorial placenta provided an almost absolute barrier to protein penetration from the foetal circulation. As other workers have described maternal-to-foetal transmission of proteins across this layer in the guinea-pig, a working hypothesis of the role of endothelium and syncytiotrophoblast in maternal/foetal protein exchange is discussed.

Animals↗
PubMed1987

A relaxing factor released by phospholipase A2 in the absence of endothelium.

Phospholipase A2 (PLA2) produced slow dose dependent relaxation in intact and endothelium-deprived precontracted rabbit aortic strips. In endothelium-deprived preparations, relaxation induced by PLA2 is inhibited by hemoglobin, methylene blue and parabromophenacylbromide (PBPB), and is potentiated by superoxide dismutase (SOD). Indomethacin has no effect. Relaxation is accompanied by a rise in c-GMP. Phospholipase C causes a significant increase in tension, while Phospholipase D has no effects. In intact aortic strips PLA2 causes a biphasic response with no elevation in c-GMP. The results indicate several common features of the PLA2 released factor with endothelium-derived relaxing factor (EDRF). However, PLA2 induced relaxation is not dependent on endothelial cells. Apparently in addition to nitric oxide which may be the endothelium-derived relaxing factor, a second smooth muscle relaxing factor exists which is initiated by PLA2 and is independent of endothelium. The production of the PLA2 produced relaxation is dependent on its specific hydrolytic activity. We call this relaxing factor the phospholipid-derived relaxing factor (PDRF).

Animals↗
PubMed1994

Anticonstrictor effect of endothelium sensitivity to shear stress.

The lumen of arterial vessels is controlled by shear stress at the endothelium; increased shear stress relaxes the smooth muscle thus evoking arterial dilatation. Since shear stress relates directly to flow rate and inversely to the third power of the internal diameter, a decrease in diameter at a constant arterial blood flow augments the shear stress which should result in smooth muscle relaxation counteracting the constriction. This anticonstrictor effect must be stronger the higher the arterial blood flow. To demonstrate the effect of endothelium sensitivity to shear stress on arterial constriction we compared constrictions of endothelium-intact femoral arteries of anaesthetized cats at different blood flow rates. An abrupt decrease in transmural pressure from 120 to 90 or 70 mm Hg at almost zero blood flow rate (where the shear stress mechanism is practically inactive) evoked a fast passive decrease in diameter with further progressive constriction. On the other hand, at flow rates of 8-15 ml/min, after passive constriction the artery began to dilate and the resultant constrictor effect appeared to be considerably smaller than in the virtual absence of flow. Analogously, responses to norepinephrine (3 x 10(-7) or 10(-6) M) were smaller the higher the blood flow. The difference in the magnitudes of the responses at different flow rates was precisely equal to the value calculated using the experimental data characterizing the diameter/flow rate relation. Endothelium removal abolished the dependence of the magnitude of the constrictor responses on blood flow. These data suggest that the endothelium sensitivity to shear stress provides considerable inhibition of arterial constrictor responses, whatever the nature of constrictor stimulus.

Animals↗