Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It is postulated that vascular disease involves a disturbance in the homeostatic balance of factors regulating vascular tone and structure. Recent developments in gene transfer techniques have emerged as an exciting therapeutic option to treat vascular disease. Several studies have established the feasibility of direct in vivo gene transfer into the vasculature by using reporter genes such as beta-galactosidase or luciferase. To date no study has documented therapeutic effects with in vivo gene transfer of a cDNA encoding a functional enzyme. This study tests the hypothesis that endothelium-derived nitric oxide is an endogenous inhibitor of vascular lesion formation. After denudation by balloon injury of the endothelium of rat carotid arteries, we restored endothelial cell nitric oxide synthase (ec-NOS) expression in the vessel wall by using the highly efficient Sendai virus/liposome in vivo gene transfer technique. ec-NOS gene transfection not only restored NO production to levels seen in normal untreated vessels but also increased vascular reactivity of the injured vessels. Neointima formation at day 14 after balloon injury was inhibited by 70%. These findings provide direct evidence that NO is an endogenous inhibitor of vascular lesion formation in vivo (by inhibiting smooth muscle cell proliferation and migration) and suggest the possibility of ec-NOS transfection as a potential therapeutic approach to treat neointimal hyperplasia.
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PMID:Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial cell nitric oxide synthase gene. 753 5

Nitric oxide (NO), derived from the vascular endothelium and other cells of the cardiovascular system, has important roles in physiological regulation of blood flow and may have pathophysiological functions in cardiovascular disease. The mechanisms involved in NO-induced vasodilatation and cytotoxicity are briefly reviewed in the context of inflammatory reactions and cardiovascular function. Although NO can hyperpolarize vascular smooth muscle, activation of the endothelium can induce hyperpolarization and vasodilatation by other means. Endogenous inhibitors of NO generated by leucocytes may compromise blood flow distribution after ischaemia and reperfusion injury. Chronic heart failure is associated simultaneously with impairment of endothelium-dependent vasodilatation and with excess production of NO via the inducible NO synthase (iNOS), although it is unclear whether the latter ameliorates or exacerbates ventricular dysfunction. Excess NO production is also one of the earliest signs of transplant rejection, and suppression of iNOS expression by immunosuppressant drugs such as cyclosporin A might be one means by which these drugs protect allografts. Disturbances in the activity of NOS isoforms in the artery wall also accompany the development of atherosclerosis, providing conditions propitious for vasospasm and thrombosis. Reversing the NO defects with therapeutic agents, including angiotensin converting enzyme (ACE) inhibitors, offers promise in protecting against some manifestations of vascular disease.
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PMID:Endogenous nitric oxide in cardiovascular disease and transplantation. 754 30

Premature atherosclerosis is a major cause of morbidity and mortality in chronic renal failure (CRF). Endothelial dysfunction is a key early event in atherogenesis. The aim of this study was to assess the effect of CRF on endothelial function using physiological and biochemical measures. To focus on the effect of CRF itself, 23 children (matched with 23 controls for age and vessel diameter) were selected because they were normotensive, had normal total cholesterol (TC) levels, and were not on vasoactive drugs. Their mean (range) age was 12.0 (7.8 to 17.0) years; GFR 17.5 (8.8 to 34.5) ml/min/1.73 m2. The physiology of endothelial function in the brachial artery was assessed using high resolution ultrasound by measuring its diameter at rest, during reactive hyperemia (endothelium dependent dilation) and after sublingual glyceryl trinitrate (GTN; endothelium independent dilation). Nitric oxide (NO) metabolites and endogenous NO synthetase (eNOS) inhibitors were measured as an assessment of endothelial metabolism. Brachial artery dilation to flow [FMD, mean (SEM)%] was reduced in CRF to 4.9 (0.6) and controls 8.6 (0.6), P < 0.0001. In contrast, the response to GTN was similar in both groups: CRF 25.1 (1.6), controls 23.3 (1.2), P = 0.31. There was no difference in TC, low density lipoprotein (LDL) or high density lipoprotein (HDL) between the patients and the controls. Triglycerides (TG) were higher in the patients but within the normal range. Antibodies against oxidized LDL (ox-LDL) were high in CRF. Endogenous NOS inhibitors were high in CRF, and intermediate NO metabolites were low. There was no correlation between FMD of the brachial artery and lipid subfractions, or with NO metabolites or eNOS inhibitors. Endothelium dependent dilation of the brachial artery is impaired in children with CRF who do not have co-existing risk factors for atherosclerosis. This may represent early evidence of atherogenic vascular disease.
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PMID:Physiology and biochemistry of endothelial function in children with chronic renal failure. 926 3

Hyperglycemia is a major cause of diabetic vascular disease. High glucose can induce reactive oxygen species (ROS) and nitric oxide (NO) generation, which can subsequently induce endothelial dysfunction. High glucose is also capable of triggering endothelial cell apoptosis. Little is known about the molecular mechanisms and the role of ROS and NO in high glucose-induced endothelial cell apoptosis. This study was designed to determine the involvement of ROS and NO in high glucose-induced endothelial cell apoptosis. Expression of endothelial nitric oxide synthase (eNOS) protein and apoptosis were studied in cultured human umbilical vein endothelial cells (HUVECs) exposed to control-level (5.5 mM) and high-level (33 mM) glucose at various periods (e.g., 2, 12, 24, 48 h). We also examined the effect of high glucose on H(2)O(2) production using flow cytometry. The results showed that eNOS protein expression was up-regulated by high glucose exposure for 2-6 h and gradually reduced after longer exposure in HUVECs. H(2)O(2) production and apoptosis, which can be reversed by vitamin C and NO donor (sodium nitroprusside), but enhanced by NOS inhibitor (N(G)-nitro-L-arginine methyl ether), were collated to a different time course (24-48 h) to HUVECs. These results provide the molecular basis for understanding that NO plays a protective role from apoptosis of HUVECs during the early stage (<24 h) of high glucose exposure, but in the late stage (>24 h), high glucose exposure leads to the imbalance of NO and ROS, resulting to the observed apoptosis. This may explain, at least in part, the impaired endothelial function and vascular complication of diabetic mellitus that would occur at late stages.
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PMID:Nitric oxide prevents apoptosis of human endothelial cells from high glucose exposure during early stage. 1050 98

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

Preeclampsia is a mainly vascular disease of pregnancy, probably caused by an imbalance between vasodilator and vasoconstrictor agents that results in generalized vasospasm and poor perfusion in many organs. Among these factors, endothelin-1 (ET-1), a potent vasoconstrictor, is highly increased in preeclamptic women, while nitric oxide (NO), a vasodilator of human utero-placental arteries, is reduced in the same patients. The present study was designed to investigate the interactions between ET-1 and the NO system in the feto-placental unit; to this purpose we also examined the messenger ribonucleic acid (mRNA) expression of ET-1, inducible NO synthase (iNOS), and endothelial NOS (eNOS) in human cultured placental trophoblastic cells obtained from preeclamptic (PE) and normotensive (NT) pregnancies. We also studied whether exogenous ET-1 may affect the expression of iNOS and eNOS in human placental trophoblastic cells. Interestingly, by Northern blot analysis we observed an increased ET-1 mRNA expression level in PE trophoblastic cells compared to NT trophoblastic cells. Furthermore, exogenous ET-1 (10(-7) mol/L) was able to up-regulate its own mRNA expression in both NT and PE trophoblastic cells. iNOS and eNOS mRNA expression was then detected, by semiquantitative PCR, in both NT and PE trophoblastic cells. PE trophoblastic cells expressed lower iNOS mRNA levels compared with NT pregnancies. On the contrary, eNOS mRNA expression was higher in PE trophoblastic cells than in NT cells. Moreover, in the presence of ET-1 we observed a decrease in iNOS and an increase in eNOS mRNA expression levels in both NT and PE trophoblastic cells compared with the respective untreated cells. In conclusion, we demonstrate that ET-1 expression is increased in PE cells, whereas iNOS, which represents the main source of NO synthesis, is decreased; conversely, eNOS expression is increased. Finally, ET-1 is able to influence its own as well as NOS isoform expression in normal and PE trophoblastic cultured cells. These findings suggest the existence of a functional relationships between ET(s) and NOS isoforms that could constitute the biological mechanism leading to the reduced placental blood flow and increased resistance to flow in the feto-maternal circulation, which are characteristic of the pathophysiology of preeclampsia.
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PMID:Expression and relationship between endothelin-1 messenger ribonucleic acid (mRNA) and inducible/endothelial nitric oxide synthase mRNA isoforms from normal and preeclamptic placentas. 1085 70

Flow-associated pulmonary hypertension leads to pulmonary plexogenic arteriopathy (PPA), a specific pulmonary vascular disease that includes vascular lesions characterized by abnormal vasodilatation and endothelial cell proliferation. Increased local production of NO has been suggested in this condition. Because reported data on the expression of endothelial NO-synthase (ecNOS) have been contradictory, we speculated that the expression of the inducible isoform of NOS (iNOS) is enhanced in this form of pulmonary hypertension. We investigated immunohistochemically the expression of ecNOS and iNOS in lung tissue of patients with flow-associated pulmonary hypertension (n = 18) and compared the findings with those in patients with increased pulmonary blood flow but normal pulmonary artery pressure (n = 10), with congestive vasculopathy (n = 6) and control subjects (n = 4). Immunoreactivity for ecNOS and iNOS was present both in normal and diseased pulmonary arteries. Marked immunoreactivity to both isoforms was present within the advanced lesions of PPA, including plexiform lesions. Semiquantitative analysis of immunoreactivity, both for ecNOS and iNOS, showed no correlation with the severity of morphologic vascular lesions (p = 0.29 and p = 0.23, respectively). In contrast to ecNOS, immunoreactivity for iNOS was increased in patients with flow-associated pulmonary hypertension compared with other patients (p = 0.02). The present study has demonstrated enhanced expression of iNOS in patients at risk for advanced PPA, but not in patients with other forms of pulmonary arteriopathy. Moreover, high expression of both ecNOS and iNOS were present in advanced lesions of PPA. These data suggest differentiated roles for different isoforms of NOS in the pathogenesis of this specific pulmonary arteriopathy.
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PMID:Altered arterial expression patterns of inducible and endothelial nitric oxide synthase in pulmonary plexogenic arteriopathy caused by congenital heart disease. 1137 23

VEGF is a key regulator of vascular permeability. However, its signaling pathways are incompletely understood. We tested the hypothesis that VEGF regulates endothelial cell (EC) permeability by activating PKB/akt, NOS, and MAP kinase dependent pathways using human umbilical vein EC (HUVEC). Permeability was measured from FITC-dextran 70-kDa flux across the EC monolayer at baseline and after VEGF at 0.034, 0.068, 1, 10, and 100 nM. VEGF increased HUVEC permeability to FITC-dextran in a dose-dependent manner. VEGF (1 nM) increased permeability from 3.9 x 10(-6) +/- 0.7 x 10(-6) to 14.0 x 10(-6) +/- 1.7 x 10(-6) cm/s (mean +/- SEM; P < 0.001). Permeability changes were also assessed after treatment with 1, 10, and 100 nM wortmannin (PI 3-kinase inhibitor); 0.01, 0.1, and 1.0 nM LY294002 (PI 3-kinase inhibitor); 200 microM l-NMMA (NOS inhibitor); 2.7 microM AG126 (p42/44(MAPK) inhibitor); and 0.006, 0.06, and 0.6 microM SB203580 (p38(MAPK) inhibitor). All inhibitors blocked VEGF-induced permeability changes. Our data demonstrate that (1) VEGF increases permeability of EC monolayers in a dose-dependent fashion, and (2) VEGF-induced permeability is mediated through PI-3 kinase-PKB, NOS, and MAP-kinase signaling cascades. These observations suggest that microvascular hyperpermeability associated with inflammation and vascular disease is mediated by activation of these EC signaling pathways.
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PMID:VEGF increases permeability of the endothelial cell monolayer by activation of PKB/akt, endothelial nitric-oxide synthase, and MAP kinase pathways. 1167 28

Exhaled nitric oxide (eNO) is thought to arise principally from the airway epithelium. NO regulates smooth muscle tone, and abnormal activity of NO synthase has been implicated in coronary artery disease (CAD). Polymorphisms of endothelial constitutive NO synthase (ecNOS) may affect NO generation and be associated with CAD. It was hypothesised that a polymorphism, such as the ecNOS intron 4 polymorphism (ecNOS4a), affects the levels of eNO via airway epithelial NOS. eNO levels were measured in 53 patients with ischaemic chest pain who had previously been genotyped for ecNOS polymorphisms, with sample enrichment for the ecNOS4a allele. Subjects were also assessed for two other ecNOS polymorphisms (T-786C substitution in the promoter region, and G5557T in exon 7), variably associated with vascular disease. Those homozygous for the 'a' allele (ecNOS4a/a) had a lower mean eNO (9.0 ppb) than those who were heterozygous (ecNOS4a/b, 13.6 ppb), who in turn had a lower level than those homozygous for the wild-type ecNOS4b/b (16.1 ppb). No association of eNO levels was found with the other polymorphisms. Levels of eNO remained significantly lower in the ecNOSa/a subjects than in the ecNOSa/b and ecNOSb/b subjects, even when controlled for angiographic CAD, and smoking habit. In addition, all subjects with CAD had a significantly lower mean eNO (12.1 ppb) than subjects without angiographic CAD (19.9 ppb). In this selected population low levels of eNO were thus associated with presence of the ecNOS4a allele and also with CAD.
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PMID:Effect of ecNOS polymorphisms and coronary artery disease upon exhaled nitric oxide. 1189 44

Estrogen is believed to protect postmenopausal women from coronary vascular disease, in part by increasing production of nitric oxide (NO). In this study, we investigated the possibility that transcriptional activation of inducible NO synthase (iNOS) is responsible for a component of the estrogen-induced increase in coronary blood flow. Twenty-two ewes were instrumented with Doppler flow probes on their left circumflex coronary and pulmonary arteries. Nine ewes received 17beta-estradiol (1 microg/kg), and the coronary vascular response was followed for 16 h. Estradiol significantly increased coronary blood flow by 22 +/- 4% over baseline and the peak response occurred at 2 h (P < 0.01). To examine the effect of estrogen on NOS expression in the ovine coronary artery, 17 noninstrumented animals were killed 2 h after administration of estradiol or vehicle. Coronary arteries were analyzed for ovine iNOS and endothelial NOS (eNOS) expression by semiquantitative RT-PCR. PCR primers were based on partial cDNA clones for ovine eNOS and iNOS isolated as part of this study. The expression of iNOS was significantly increased (27-fold) by the administration of estradiol, whereas the expression of eNOS was much weaker (2-fold). To confirm these effects in vivo, additional instrumented animals received either the estrogen receptor (ER) antagonist ICI-182,780 (n = 5), the iNOS antagonist dexamethasone (n = 5), or pyrrolidine dithiocarbamic acid, an inhibitor of nuclear factor-kappaB (n = 5). All three antagonists inhibited estrogen-induced increases in coronary blood flow and increases in cardiac output by over 85%. These results strongly support the hypothesis that 17beta-estradiol increases coronary blood flow in the unanesthetized nonpregnant ewe via an ER-dependent mechanism that results in an increase in both eNOS and iNOS expression.
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PMID:Estrogen increases iNOS expression in the ovine coronary artery. 1218 Nov 48


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