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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The vascular endothelial cell is a multipotent cell which has several functions: transport barrier, phagocytosis, coagulation/anticoagulation, fibrinolysis, autocrine/paracrine and metabolic functions. The release of vasoactive agents, such as the vasodilators EDRF (NO) and EDHF, and vasoconstrictors, such as endothelin (ET), represents an important local mechanism altering the balance of vasodilation/ vasoconstriction of the vascular smooth muscle cell. Inhibition of the synthesis of NO by exogenous (e.g. L-NAME) or endogenous (e.g. ADMA) L-arginine analogues may cause transient or sustained hypertension. A similar effect may be achieved by continuous administration of the potent vasoconstrictor ET. Endothelial dysfunction, associated with a deficient NO production and release as well an enhanced ET generation, may be present in some forms of vascular disease, such as hypertension, atherosclerosis, diabetes mellitus or sleep apnea. Whether such alterations may be a cause of hypertension and involved in the maintenance of high blood pressure or whether they represent a consequence of the hypertensive disease remains to be concluded. Furthermore, while there is emerging evidence that endothelial dysfunction in cardiovascular disease may be reversed by therapy, it remains to be determined whether measures of endothelial function in man may serve as predictors for morbidity or mortality.
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PMID:Measures of endothelial function as an endpoint in hypertension? 949 29

Mammalian endothelium acts as a mediator in arterial and venous relaxation and contraction. Endothelium-dependent relaxation is due to endothelial release of powerful, non-prostanoid vasodilatory substances. The best known of these is the endothelial factor EDRF identified as nitrous oxide (NO). It is the end result of the metabolism of L-arginine by the NO synthetase of endothelial cells. In arterial smooth muscle, the relaxation induced by EDRF is explained by NO stimulation of soluble guanylate cyclase, leading to accumulation of GMPc (cyclic guanosine monophosphate). In some animal vessels and in human coronary arteries, endothelial cells release a substance which induces hyperpolarisation of the cell membrane (endothelial derived hyperpolarising factor, EDHF). Release of EDRF by the cell membrane may be mediated by G proteins sensitive to pertussis toxin (activation of the alpha 2 adrenoreceptor, serotonin, platelet aggregation, leukotrienes) or non-sensitive G proteins (adenosine-diphosphate (ADP), bradykinin). In animal blood vessels where the endothelium is regenerated and reperfused, and/or atherosclerotic, a selective loss of the mechanism of EDRF release is observed, sensitive to pertussis toxin, which favors vasospasm, thrombosis and cellular proliferation. The available data on isolated or in situ human blood vessels concord with studies on isolated animal tissues. In addition to the relaxation factors, endothelial cells can also secrete contracting factors (endothelium derived contracting factors: EDCF); these include superoxide anions, endoperoxides, thromboxane A2 and endothelin. Animal studies indicate that the tendency to release EDCF is maintained or even increased in damaged vessels. The change from normally dominant EDRF release to EDCF release could play an important role in atherosclerosis.
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PMID:[Endothelial dysfunction and atherosclerosis]. 951 9

The endothelium is a major regulator of vascular tone, releasing vasoactive substances such as endothelium-derived nitric oxide (EDRF), endothelium-derived hyperpolarizing factor(s), cycloxygenase metabolites, endothelin and other endothelium-derived contracting factors (EDCF). In a number of cardiovascular pathologies, such as hypertension or heart failure, the balance in the endothelial production of vasodilating and vasoconstricting mediators is altered. The resulting apparent decrease in endothelium-dependent relaxations is termed 'endothelial dysfunction'. In hypertensive patients and in animal models of hypertension, endothelium-dependent relaxations are impaired. However, this endothelial dysfunction presents different characteristics depending on the model studied. In Dahl-salt-sensitive rats, the decrease in endothelium-dependent relaxations is associated with impaired constitutive nitric oxide synthase activity. The presence of an endogenous nitric oxide synthase inhibitor and a decreased response of vascular smooth muscle to the mediator may contribute also to the dysfunction observed in this model. In other animal models of hypertension (such as spontaneous hypertension). the contribution of the L-arginine nitric oxide pathway to endothelium-dependent responses appears normal or impaired despite reports of increased nitric oxide synthase activity or expression. In large arteries from SHR, endothelium-dependent relaxations are impaired mainly because of the concomitant augmented release of endoperoxides activating thromboxane-endoperoxide receptors. Superoxide anions may also play a role in some models, but only in the early phase of the disease: whether or not these species contribute to further development of endothelial dysfunction or to increases in blood pressure remains to be examined. The endothelial dysfunction observed in hypertension is likely to be a consequence of high blood pressure. but it could facilitate the maintenance of elevated peripheral resistance at a later stage in the disease and favour the occurrence of complications, such as atherosclerosis.
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PMID:Secondary endothelial dysfunction: hypertension and heart failure. 1007 14

Furchgott et al. demonstrated in 1980 that relaxation of arterial smooth muscle cells in response to acetylcholine is dependent on the integrity of endothelium. They named the factor responsible of this intercellular relationship EDRF (Endothelium Derived Relaxing Factor), which was identified 7 years latter as nitric oxide (NO), a free radical gas. In vessels, NO is generated locally by the endothelial NO synthase and its effect is mainly paracrine (relaxation of the underlying smooth muscle cells, and inhibition of platelet aggregation). The in vivo half-life of NO is short, and the assessment of its production is thus difficult. Invasive and non invasive techniques are now available to explore the variations of arterial diameter or flow. Furchgott's pioneering work anticipated the whole pathophysiology of endothelial-dependent relaxation. Indeed, numerous diseases, in particular atherosclerosis, are accompanied by abnormalities of endothelial-dependent vasodilation ("endothelial dysfunction"). Whereas acetylcholine (or serotonin) infused in a normal artery elicits a vasodilation, in contrast, it promotes a vasoconstriction in an atheromatous artery, as a consequence of a decrease in NO bioavailability. This defect in NO favors arterial spasm, interaction between platelets and arterial wall and thrombosis, and thus probably cardiovascular events. NO cannot be measured directly in humans, except in exhaled NO. In vivo, NO is rapidly oxidized in nitrite (NO2-) and in nitrate (NO3-), the summation being NOx. We shall detail the limitations of this measurement as a biochemical index of NO production from "endothelial" origin.
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PMID:[Clinical and biological investigation of NO]. 1132 17

In this study the synergistic role of the two haemodynamic parameters, pressure and wall shear stress, in macromolecular transport has been examined across the wall of the rabbit thoracic aorta. Arteries were subjected to 70 and 150 cm water pressure in the presence of fluid flow imposed shear stress. The flux of FITC labelled bovine serum albumin was found to be 3.36+/-1.34 x 10(-6) and 1.99+/-0.77 x 10(-6) cm/s (mean+/-S.D.) after 90 min incubation at 70 and 150 cm water, respectively. The mean relative tissue concentrations were 0.0039+/-0.0025 and 0.012+/-0.007 at 70 and 150 cm water, respectively. Under low values of steady wall shear stress, efflux of BSA is retarded at 150 cm since its tissue concentration is found to be higher than at 70 cm. The net outcome arises as a result of the interaction of increased permeability of endothelial cells exposed to shear stress, the pressure induced distension of the wall matrix and the differential effect of EDRF/NO at the two pressures on medial hydraulic conductivity. In the presence of the EDRF/NO inhibitor L-NAME, reduction in flux of albumin was observed at both the pressures, the decrease being greater at 150 cm water. In the absence of EDRF, the NO synthase independent vasodilator EDHF may be released, which maintains the tone of the medial smooth muscle low. Action of EDHF may be more marked at 150 cm water because NO synthesis is attenuated by higher transmural pressure and the presence of L-NAME eliminates shear stress stimulated NO release. Consequently the dilated vessel will have decreased porosity and less albumin space. The BSA flux across the aorta is, therefore, influenced by both endothelial permeability and permeability of the medial matrix, which are in turn modulated by an interplay of transmural pressure and fluid flow generated shear stress.
Atherosclerosis 2001 Jun
PMID:Interaction of transmural pressure and shear stress in the transport of albumin across the rabbit aortic wall. 1139 28

Oxidized low-density lipoprotein (Ox-LDL) is an atherogenic lipoprotein. It has been suggested that Ox-LDL causes endothelial dysfunction by decreasing the release of endothelium-derived factors (EDRF-NO) or increasing the inactivation of EDRF-NO. The mechanism by which Ox-LDL causes dysfunctional NO during early stages of atherosclerosis is not clear. The purpose of this study was to examine the role of Ox-LDL on nitric oxide synthetase (eNOS), protein kinase C (PKC) activities and cAMP production in bovine aortic endothelial cells (BAEC). Ox-LDL stimulated PKC activity of BAEC but it inhibited both eNOS activity and cAMP production. Ox-LDL partially inhibited the forskolin stimulated cAMP production. Furthermore, we observed that 8Br-cAMP treatment decreased the activity of eNOS in a concentration dependent manner. Serotonin which has a profound inhibitory effect on cAMP production also stimulated eNOS activity. Pertusis toxin treatment blocked the stimulatory action of serotonin on the stimulation of eNOS activity. Our results thus suggest that Ox-LDL inhibit the endothelium-dependent relaxation. One possible mechanism is that Ox-LDL stimulates PKC activity, which in turn increases the phosphorylation of the Gi-protein. Inhibition of Gi-protein then leads to reduced release of NO from endothelial cells and thus causes endothelial dysfunction.
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PMID:Effects of oxidized low density lipoprotein on nitric oxide synthetase and protein kinase C activities in bovine endothelial cells. 1178 56

We investigated whether endothelium-derived relaxing (EDRF) and hyperpolarizing factor (EDHF) is impaired in type 2 diabetic rats (Otsuka Long-Evans Tokushima Fatty (OLETF) rat) and whether the exercise training improves impaired EDRF and EDHF. Diabetic rats were divided into the sedentary and exercise-trained groups at the age of 16 weeks. Long-Evans Tokushima Otsuka (LETO) rats were used as age-matched non-diabetic controls. EDRF as well as EDHF induced by acetylcholine in the presence of indomethacine and L-nitro N-arginine was significantly attenuated in the diabetic rats, and was further impaired with age. Exercise training significantly improved it. Both insulin resistance and abdominal fat accumulation were significantly greater in the diabetic rats, compared with the non-diabetic rats, but were decreased in exercise-trained rats. Urinary NO(2) secretion was decrease in the diabetic rats at each age, and it was improved by exercise training. The results of the study indicated that exercise training prevented impairment of EDHF, as well as EDRF in type 2 diabetic rats, presumably due to improvement of hyperglycemia and insulin resistance and increase in the production of nitric oxide by exercise training.
Atherosclerosis 2002 May
PMID:Exercise training improves acetylcholine-induced endothelium-dependent hyperpolarization in type 2 diabetic rats, Otsuka Long-Evans Tokushima fatty rats. 1194 1

Endothelial injuries induced by different stimuli lead to proliferation of intimal vascular smooth muscle cells with formation of neointima. In this functional study, we evaluated the reactivity to contracting and vasorelaxing agents in Wistar rat carotid artery at different times (1, 7, 14, 21 and 28 days) after endothelial denudation with angioplastic balloon technique. Injured (IC) and uninjured carotid artery rings (UC) were placed in an isolated organ bath for isometric force displacement. IC collected at 1, 7, 14, 21 and 28 days showed a reduction in contraction to phenylephrine (0.3 microM), angiotensin II (0.1 microM), U46619 (0.1 microM), KCl (60 mM) and A23187 (1microM) at any experimental time compared to rings obtained from UC. The evaluation of endothelial-derived relaxing or hyperpolarizing factor (EDRF or EDHF), induced by acetylcholine (0.001-1 microM) in presence of indomethacin (10 microM) or indomethacin and Nomega-nitro-L-arginine methyl ester hydrochloride (L-NAME) (10 and 100 microM, respectively), was carried out at 14, 21 and 28 days. The EDRF-induced relaxation was significantly (P < 0.0001) reduced at 14 days and it improved through out the observation time, indeed at 28 days it was indistinguishable from UC relaxation curve. In contrast, the EDHF-induced relaxation was significantly (P < 0.0001) reduced at all experimental time. A significant reduction in nitric oxide-induced relaxation, sodium nitroprusside (0.001-10 microM), was observed at 7, 14 and 21 days, but not at 28 days. The relaxation induced by diazoxide (3-300 microM), an opener of KATP channels, was significantly reduced only at 7 days but not at 14, 21 and 28 days. Western blot analysis of myosin heavy chain revealed that up to 28 days the re-differentiation (maturity state) of smooth muscle cells was not yet reached. In conclusion, our data showed that hyporeactivity to contracting and relaxing agents in endothelial denuded carotid of rats could be linked to a multifactorial condition in which reduction of receptors and alterations in post-receptor transductions in neointima may produce modification of protein expression and/or variation in ion flux where calcium could have a pivotal role.
Atherosclerosis 2003 Dec
PMID:Time course of vascular reactivity to contracting and relaxing agents after endothelial denudation by balloon angioplasty in rat carotid artery. 1464 85

Healthy vascular function is primarily regulated by several factors including EDRF (endothelium-dependent relaxing factor), EDCF (endothelium-dependent contracting factor) and EDHF (endothelium-dependent hyperpolarizing factor). Vascular dysfunction or injury induced by aging, smoking, inflammation, trauma, hyperlipidaemia and hyperglycaemia are among a myriad of risk factors that may contribute to the pathogenesis of many cardiovascular diseases, such as hypertension, diabetes and atherosclerosis. However, the exact mechanisms underlying the impaired vascular activity remain unresolved and there is no current scientific consensus. Accumulating evidence suggests that the inflammatory cytokine TNF (tumour necrosis factor)-alpha plays a pivotal role in the disruption of macrovascular and microvascular circulation both in vivo and in vitro. AGEs (advanced glycation end-products)/RAGE (receptor for AGEs), LOX-1 [lectin-like oxidized low-density lipoprotein receptor-1) and NF-kappaB (nuclear factor kappaB) signalling play key roles in TNF-alpha expression through an increase in circulating and/or local vascular TNF-alpha production. The increase in TNF-alpha expression induces the production of ROS (reactive oxygen species), resulting in endothelial dysfunction in many pathophysiological conditions. Lipid metabolism, dietary supplements and physical activity affect TNF-alpha expression. The interaction between TNF-alpha and stem cells is also important in terms of vascular repair or regeneration. Careful scrutiny of these factors may help elucidate the mechanisms that induce vascular dysfunction. The focus of the present review is to summarize recent evidence showing the role of TNF-alpha in vascular dysfunction in cardiovascular disease. We believe these findings may prompt new directions for targeting inflammation in future therapies.
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PMID:Role of TNF-alpha in vascular dysfunction. 1911 93

Purinergic signalling is involved in the control of vascular tone and remodelling. Endothelial cells release purines and pyrimidines in response to changes in blood flow (evoking shear stress) and hypoxia. They then act on P2Y, P2X and P1 receptors on endothelial cells leading to release of EDRF mediated by nitric oxide and prostaglandins and EDHF, resulting in vasodilatation. The therapeutic potential of purinergic compounds for the treatment of vascular diseases, including hypertension, ischaemia, atherosclerosis, migraine and coronary artery and diabetic vascular disease as well as vasospasm is discussed.
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PMID:Purinergic Signalling and Endothelium. 2663 99


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