UMLS:C0042373 - FACTA Search

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Query: UMLS:C0042373 (vascular disease)
17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Obesity and insulin resistance are strongly associated with an increased risk of vascular disease. Vasomotion is the cyclic variation in the diameter of arteries and is a general feature of the vasculature that may have important physiological consequences. We tested the hypothesis that obesity - insulin resistance is associated with abnormal vasomotion by comparing obese, insulin-resistant JCR:LA-cp rats, known to develop vasculopathy, atherosclerosis, and ischemic lesions of the heart, with lean insulin-sensitive animals from the same strain. Vasomotion was assessed using isolated mesenteric arteries on a myograph system after preconstriction to 50% of maximal constriction with norepinephrine. The amplitude of vasomotion was enhanced by the presence of meclofenamate, a prostaglandin H synthase inhibitor, and was diminished by N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor. Removal of the endothelium essentially abolished vasomotion, and meclofenamate had no effect on de-endothelialized arteries. Frequency was not altered by either L-NAME or meclofenamate. Although pharmacological inhibition of nitric oxide and eicosanoid production clearly altered vasomotion, there was no difference in the amplitude or frequency of vasomotion in arteries from obese rats compared with lean rats. These results indicate that the endothelium plays a central role in modulating vasomotion, involving both enhancing and inhibiting effects, and that vasomotion is similar between obese, insulin-resistant and lean, insulin-sensitive rats.
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PMID:Modulation of vasomotion in resistance arteries of JCR:LA-cp rats: a model of insulin resistance. 1053 69

The normal endothelium is characterised by the production of a number of molecules which affect the contractile state of adjacent myocytes and the behavior of formed elements within the blood stream, and by the absence of cell surface adhesion molecules. In addition, endothelial cells are important modulators of coagulation and fibrinolysis. Whilst effects of lipids have been documented on many of these endothelial processes, there is particularly strong evidence for effects on the vasodilatation mediated by endothelium derived nitric oxide and on the interaction between leukocytes and the endothelial surface. Both LDL cholesterol and triglyceride rich lipoproteins impair endothelium dependent vasodilatation. The effects of LDL cholesterol are primarily evident for lipoprotein particles that have been oxidised with evidence for effects of specific constituents of oxidised LDL, such as lysophosphatidylcholine (LPC). LDL effects have been demonstrated at numerous sites of the nitric oxide signaling pathway including receptor-G protein coupling, nitric oxide synthase and NO bioactivity, with evidence for enhanced superoxide formation and the consequent production of the less potent dilator peroxynitrite. The effects of lipids on endothelium dependent vasodilatation can be reversed not only by reducing the level of elevated lipids levels but also by provision of the NOS substrate, L-arginine and by the provision of antioxidants, although the mechanism for these effects are not fully elucidated. The adhesion of leukocytes to the endothelial surface is stimulated by low density and triglyceride rich lipoproteins. As with endothelium dependent vasodilatation, the effects of LDL cholesterol are primarily evident for low-density lipoprotein particles that have been oxidised, and many of the effects of oxidised LDL can be mimicked by LPC. HDL can overcome pro-adhesive effects of oxidised LDL. The effects of LDL on leukocyte adhesion are secondary to the expression of adhesion molecules on the luminal surfaces of endothelial cells. In addition to the likely deleterious effects of lipids on endothelium-mediated vasodilatation and leukocyte-endothelial cell interaction, lipids have been shown to affect a number of other endothelial processes and function. Thus, oxidised LDL affects endothelial ET1 and PGI2 release. Although effects have been shown on endothelial cell growth and apoptosis and on endothelial processes related to thrombosis and fibrinolysis, these effects have been less extensively studied than endothelial dependent vasodilatation and leukocyte-endothelial cell interaction. Many of the effects of elevated or modified low density and TG rich lipoproteins on endothelial cells and endothelial cell processes could be expected to contribute to the development of atherosclerosis and therefore, to the association between lipids and atherosclerotic, particularly coronary, vascular disease. However, the extent to which "endothelial dysfunction" accounts for the known relationships between serum lipid concentrations and CHD is yet to be established.
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PMID:Lipids and the endothelium. 1053 61

Increased beta-amyloid production is believed to play a central role in the pathogenesis of Alzheimer's disease. Amyloid is deposited not only in the brain of Alzheimer patients as senile plaques but also in the cerebral vessel wall leading to cerebral amyloid angiopathy. Freshly solubilised amyloid beta-(1-40) was previously reported to exert a vasoconstrictor effect. We investigated whether amyloid beta-(1-40) affects the nitric oxide (NO)/cyclic GMP pathway in primary cultured endothelial cells from bovine aorta and rat coronary microvessels. Surprisingly, a significant increase in cyclic GMP production after incubation with freshly dissolved amyloid beta-(1-40) was found. The stimulation of cyclic GMP production could be inhibited by the bradykinin B(2) receptor antagonist icatibant, the NO synthase inhibitor N-omega-nitro-L-arginine, the serine protease inhibitor 3, 4-dichloroisocoumarin and the selective plasma kallikrein inhibitor Pefabloc PK, suggesting activation of the plasma kallikrein-kinin system. This is supported by a three- to four-fold increase in kinins in the supernatant of both types of endothelial cells after incubation with amyloid beta-(1-40) at concentrations of 10(-7) and 10(-6) mol/l.
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PMID:Amyloid beta-(1-40) stimulates cyclic GMP production via release of kinins in primary cultured endothelial cells. 1055 1

Hypertension and vascular disease are common complications in autosomal-dominant polycystic kidney disease (ADPKD). The role of changes in morphology and reactivity of resistance vessels in this disease have not previously been studied. Mesenteric resistance arteries were dissected from 8- to 14-week-old heterozygous Han:SPRD polycystic kidney disease (PKD) rats, homozygous normal Han:SPRD littermates (HSPRD) and Sprague-Dawley rats (SD). The morphology, noradrenaline (NA) contractility, endothelium-dependent acetylcholine (ACh) relaxation before and after incubation with L(G)-nitro-L-arginine methyl ester (L-NAME), and endothelium-independent 3-morphollino-sydnonimine (SIN-1) relaxation were studied with the Mulvany-Halpern myograph. Blood pressure and morphology of vessels were the same in all groups of rats, apart from a slightly higher media/lumen ratio in heterozygous PKD rats (p < 0.05). Active wall tension and contractile sensitivity to NA were higher in both heterozygous PKD rats and HSPRD than SD rats (p < 0. 05). The maximum endothelium-dependent relaxation rate was markedly decreased in heterozygous PKD (19 +/- 9%) and HSPRD (34 +/- 12%) compared to SD rats (75 +/- 11%) (p < 0.05). After incubation with L-NAME, ACh-induced relaxation was significantly attenuated in SD rats, less attenuated in HSPRD, and not significantly changed in heterozygous PKD rats. SIN-1-induced endothelium-independent relaxation was similar in all three groups. In conclusion, hyperreactivity to NA and impaired endothelium-dependent relaxation were present in resistance vessels from Han:SPRD rats, especially in animals with PKD. These abnormalities in resistance vessels from PKD rats may be important for the development of hypertension and vascular disease.
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PMID:Contractility and endothelium-dependent relaxation of resistance vessels in polycystic kidney disease rats. 1062 26

Nitric oxide (NO) is synthesized by at least three distinct isoforms of NO synthase (NOS). Their substrate and cofactor requirements are very similar. All three isoforms have some implications, physiological or pathophysiological, in the cardiovascular system. The endothelial NOS III is physiologically important for vascular homeostasis, keeping the vasculature dilated, protecting the intima from platelet aggregates and leukocyte adhesion, and preventing smooth muscle proliferation. Central and peripheral neuronal NOS I may also contribute to blood pressure regulation. Vascular disease associated with hypercholesterolaemia, diabetes, and hypertension is characterized by endothelial dysfunction and reduced endothelium-mediated vasodilation. Oxidative stress and the inactivation of NO by superoxide anions play an important role in these disease states. Supplementation of the NOS substrate L-arginine can improve endothelial dysfunction in animals and man. Also, the addition of the NOS cofactor (6R)-5,6,7, 8-tetrahydrobiopterin improves endothelium-mediated vasodilation in certain disease states. In cerebrovascular stroke, neuronal NOS I and cytokine-inducible NOS II play a key role in neurodegeneration, whereas endothelial NOS III is important for maintaining cerebral blood flow and preventing neuronal injury. In sepsis, NOS II is induced in the vascular wall by bacterial endotoxin and/or cytokines. NOS II produces large amounts of NO, which is an important mediator of endotoxin-induced arteriolar vasodilatation, hypotension, and shock.
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PMID:Nitric oxide in the pathogenesis of vascular disease. 1068 59

Homocysteine found in the plasma of patients with coronary heart disease, induces vascular smooth muscle cell (VSMC) proliferation and increases deposition of extracellular matrix (ECM) components. Yet, the mechanism by which homocysteine mediates this effect and its role in vascular disease is largely unknown. We hypothesized that homocysteine induces ECM production via intracellular calcium release in VSMC. To test this hypothesis, aortic VSMC from Sprague-Dawley rats were isolated and characterized by positive labeling for vascular smooth muscle alpha-actin. Early passage cells (p2-3) were grown in monolayer on coverslips. Calcium transients were quantified with fura2/AM spectrofluorometry. Homocysteine induced intracellular calcium [Ca(2+)](i) transients with an EC(50) of 60 +/- 5 nM. The EC(50) for glutathione and cysteine were 10 and 100-fold lower, respectively. Depleting extracellular calcium did not alter the homocysteine effect on intracellular calcium; however, thapsigargin pretreatment, which depletes intracellular Ca(2+) stores, abolished the homocysteine effect, demonstrating its dependence on intracellular Ca(2+) stores. Extracellular sodium depletion significantly (P < 0.05) increased [Ca(2+)](i) also suggesting a possible role of sodium-calcium exchange in the process. To begin to elucidate the intracellular pathways by which homocysteine might act, VSMC were pretreated with specific inhibitors and stimulators prior to homocysteine stimulation. Staurosporine and phorbol myrisate acetate (PMA), potent simulators of protein kinase C, augmented the release of Ca(2+) by homocysteine. Interestingly, pretreatment with the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) greatly exacerbated the sensitivity of VSMC to homocysteine. In contrast, pretreatment with either the phospholipase A(2) activator neomycin, the antioxidant and hepatic hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase inhibitor, pravastatin, the tyrosine kinase inhibitor genestein, or the calcium channel blocker, felodipine completely inhibited the homocysteine-induced Ca(2+) signal in VSMC. This suggests the role of multiple signaling pathways in the homocysteine effect on VSMC Ca(2+). Effects of homocysteine on collagen production, as ascertained by immunoblot analysis, correlated with its effect in intracellular calcium. Regardless of the signaling pathways involved, homocysteine, by virtue of its role on VSMC proliferation and ECM deposition, has the potential to affect vascular reactivity. To determine the effect of homocysteine on the ability of VSMC to react to potent agonist such as angiotensin II, VSMC were pretreated with homocysteine and exposed to a range of angiotensin II concentrations which normally have no effect on intracellular Ca(2+). After homocysteine pretreatment, VSMC were extremely responsive to angiotensin II at concentrations well below the physiologic range. These data taken together suggested that an initial effect of homocysteine is to induce release of intracellular Ca(2+) in VSMC and may induce vascular reactivity. The transient in Ca(2+) correlates with the effect on ECM associated with homocysteine.
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PMID:Homocyst(e)ine induces calcium second messenger in vascular smooth muscle cells. 1069 63

Ascorbic acid enhances NO bioactivity in patients with vascular disease through unclear mechanism(s). We investigated the role of intracellular ascorbic acid in endothelium-derived NO bioactivity. Incubation of porcine aortic endothelial cells (PAECs) with ascorbic acid produced time- and dose-dependent intracellular ascorbic acid accumulation that enhanced NO bioactivity by 70% measured as A23187-induced cGMP accumulation. This effect was due to enhanced NO production because ascorbate stimulated both PAEC nitrogen oxide (NO(2)(-) + NO(3)(-)) production and l-arginine to l-citrulline conversion by 59 and 72%, respectively, without altering the cGMP response to authentic NO. Ascorbic acid also stimulated the catalytic activity of eNOS derived from either PAEC membrane fractions or baculovirus-infected Sf9 cells. Ascorbic acid enhanced bovine eNOS V(max) by approximately 50% without altering the K(m) for l-arginine. The effect of ascorbate was tetrahydrobiopterin (BH(4))-dependent, because ascorbate was ineffective with BH(4) concentrations >10 microm or in PAECs treated with sepiapterin to increase intracellular BH(4). The effect of ascorbic acid was also specific because A23187-stimulated cGMP accumulation in PAECs was insensitive to intracellular glutathione manipulation and only ascorbic acid, not glutathione, increased the intracellular concentration of BH(4). These data suggest that ascorbic acid enhances NO bioactivity in a BH(4)-dependent manner by increasing intracellular BH(4) content.
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PMID:Ascorbic acid enhances endothelial nitric-oxide synthase activity by increasing intracellular tetrahydrobiopterin. 1074 76

Nitric oxide (NO) induces vasodilatatory, antiaggregatory, and antiproliferative effects in vitro. To delineate potential beneficial effects of NO in preventing vascular disease in vivo, we generated transgenic mice overexpressing human erythropoietin. These animals induce polyglobulia known to be associated with a high incidence of vascular disease. Despite hematocrit levels of 80%, adult transgenic mice did not develop hypertension or thromboembolism. Endothelial NO synthase levels, NO-mediated endothelium-dependent relaxation and circulating and vascular tissue NO levels were markedly increased. Administration of the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) led to vasoconstriction of peripheral resistance vessels, hypertension, and death of transgenic mice, whereas wild-type siblings developed hypertension but did not show increased mortality. L-NAME-treated polyglobulic mice revealed acute left ventricular dilatation and vascular engorgement associated with pulmonary congestion and hemorrhage. In conclusion, we here unequivocally demonstrate that endothelial NO maintains normotension, prevents cardiovascular dysfunction, and critically determines survival in vivo under conditions of increased hematocrit.
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PMID:Nitric oxide prevents cardiovascular disease and determines survival in polyglobulic mice overexpressing erythropoietin. 1102 59

Elevated homocysteine levels have been associated with arteriosclerosis and thrombosis. Hyperhomocysteinemia is caused by altered functioning of enzymes of its metabolism due to either inherited or acquired factors. Betaine-homocysteine methyltransferase (BHMT) serves, next to methionine synthase, as a facilitator of methyl group donation for remethylation of homocysteine into methionine, and reduced functioning of BHMT could theoretically result in elevated homocysteine levels. Recently, the genomic sequence of the BHMT gene was published. Mutation analysis may reveal mutations of the BHMT gene that could lead to hyperhomocysteinemia. In the present study we performed genomic sequencing of the BHMT gene of 16 vascular patients with hyperhomocysteinemia and detected three mutations in the coding region of this gene. The first was an amino acid substitution of glycine to serine (G199S), which was found only in the heterozygous state. The second mutation was a substitution of glutamine to arginine (Q239R), and the last mutation was an amino acid substitution of glutamine to histidine (Q406H). The latter was also found only in the heterozygous state. The relevance of these mutations was tested in a study group, which consists of 190 cases with vascular disease and 601 controls. The influence of these three mutations on homocysteine levels was investigated. None of the three mutations led to significantly changed homocysteine levels. In addition, no differences in genotype distribution between cases and controls were found. So far, our results provide no evidence for a role of defective BHMT functioning in hyperhomocysteinemia or subsequently in vascular disease.
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PMID:Betaine-homocysteine methyltransferase (BHMT): genomic sequencing and relevance to hyperhomocysteinemia and vascular disease in humans. 1107 19

Alterations in the synthesis or enhanced inactivation of nitric oxide (NO) and an increase in endothelin-1 production lead to an imbalance that can induce arterial hypertension. Type II diabetes is characterized by impaired endothelium-dependent vasodilation and vascular disease. NO is produced through L-arginine pathway by three different isoforms of nitric oxide synthase (NOS), an inducible form that can be activated by cytokines such as tumor necrosis factor alpha (TNFalpha). We evaluated NO plasmatic levels, endothelial damage markers such as von Willebrand factor (vWF), platelet activation, soluble P-selectin (sP-Sel), TNFalpha levels, insulinaemia (I), glycosylated haemoglobin (HbA1c), glycaemia and blood pressure in 32 hypertensive diabetic type II patients (Group A), 37 hypertensive patients (Group B) and 35 healthy subjects (Group C) matched in sex, age, body mass index and dietary habits. The level of I was increased in patients compared to the controls and correlated with their NO levels. vWF plasmatic levels were increased in Group A compared to Groups B and C. We also found significant differences in platelet activation among all the groups. In diabetic patients, increased NO levels correlated with TNFalpha, HbA1c and platelet activation showed greater endothelial damage than in Group B. These parameters described a prothrombotic state associated with an insulin resistance state, an increased vWF release, raised sP-Sel and TNFalpha levels and, maybe, low NO bioavailability, which could lead to a higher risk of development of thrombotic events in hypertensive diabetic patients (Group A) than in the hypertensive patients in Group B.
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PMID:Endothelial dysfunction, nitric oxide and platelet activation in hypertensive and diabetic type II patients. 1132 20

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