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PubMed2007

A single loading dose of clopidogrel causes dose-dependent improvement of endothelial dysfunction in patients with stable coronary artery disease: results of a double-blind, randomized study.

Clinical studies have demonstrated beneficial effects for clopidogrel in patients with atherothrombotic disease. Recent in vitro studies identified stimulating effects of clopidogrel on endothelial cells, pointing towards mechanisms of action beyond the inhibition of platelet aggregation. We hypothesized that in vivo use of clopidogrel improves endothelial dysfunction in patients with coronary artery disease (CAD). Fifty-eight patients with CAD were randomly assigned to double-blinded oral administration of one single dose of clopidogrel 300 mg (C300) or 600 mg (C600), respectively. Endothelial function was assessed by measurement of flow-mediated dilation (FMD) of the brachial artery before and 2, 4 and 22 h after dose administration, respectively. Inhibition of the platelet ADP P2Y12 receptor by clopidogrel was monitored by the ex vivo analysis of ADP effects on prostaglandin-induced platelet VASP phosphorylation. C600 significantly improved FMD at 2, 4 and 22 h, while C300 significantly improved FMD at 4 and 22 h. Clopidogrel dose- and time-dependently inhibited the platelet ADP P2Y12 receptor without correlation with its stimulatory effects on FMD. Our study demonstrates for the first time in vivo that clopidogrel dose-dependently improves endothelial dysfunction. These results may indicate a new and potentially important aspect of the effect of clopidogrel treatment in patients with CAD.

Aged↗

PubMed2002

Increased urinary albumin excretion, endothelial dysfunction, and chronic low-grade inflammation in type 2 diabetes: progressive, interrelated, and independently associated with risk of death.

In 328 type 2 diabetic patients followed for 9.0 years (mean), we investigated whether endothelial dysfunction and chronic inflammation (estimated from plasma markers) can explain the association between (micro)albuminuria and mortality. Of the patients, 113 died. Mortality was increased in patients with baseline microalbuminuria or macroalbuminuria (odds ratios as compared with normoalbuminuria, 1.78 [P < 0.05] and 2.86 [P < 0.01]) and in patients with soluble vascular cell adhesion molecule 1 in the third tertile and C-reactive protein in the second and third tertiles (odds ratios as compared with the first tertile, 2.05 [ P < 0.01], and 1.80 [P < 0.05] and 2.92 [ P < 0.01]). These associations were mutually independent. The mean yearly change in urinary albumin excretion was 9.4%; in von Willebrand factor, 8.1%; in tissue-type plasminogen activator, 2.8%; in soluble vascular cell adhesion molecule 1, 5.2%; in soluble E-selectin, -2.3%; in C-reactive protein, 3.8%; and in fibrinogen, 2.3%. The longitudinal development of urinary albumin excretion was significantly and independently determined by baseline levels of and the longitudinal development of BMI, systolic blood pressure, serum creatinine, glycated hemoglobin and plasma von Willebrand factor (baseline only), soluble E-selectin (baseline only), tissue-type plasminogen activator, C-reactive protein, and fibrinogen. The longitudinal developments of markers of endothelial function and inflammation were interrelated. In type 2 diabetes, increased urinary albumin excretion, endothelial dysfunction, and chronic inflammation are interrelated processes that develop in parallel, progress with time, and are strongly and independently associated with risk of death.

Albuminuria↗

PubMed2001

[Homocysteine, endothelial dysfunction and cardiovascular risk: pathomechanisms and therapeutic options].

Elevated homocyst(e)ine plasma concentrations are an independent risk factor for cardiovascular disease. Hyperhomocyst(e)inaemia is common in patients with peripheral arterial occlusive disease, coronary heart disease, cerebrovascular disease, carotid artery stenosis and venous thromboembolism. Endothelial dysfunction may be one underlying cause leading to proatherogenic effects associated with hyperhomocyst(e)inaemia. However, the mechanisms which lead to impaired endothelial function in hyperhomocyst(e)inaemia are not fully understood. Recent evidence suggests that homocyst(e)ine may interact with physiological mediators of the endothelial matrix. Oxidative mechanisms and decreased biological activity of endothelium-derived nitric oxide (NO) may also contribute to homocyst(e)ine-associated endothelial dysfunction. B vitamins are essential cofactors in the metabolism of homocyst(e)ine to methionine via the remethylation-pathway (vitamin B12, folic acid) and to cystathionine via the transsulphuration-pathway (vitamin B6). Dietary deficiencies of folic acid, vitamin B12, and vitamin B6 appear to be common among elderly people in the western world and represent one pathogenic factor related to the incidence of hyperhomocyst(e)inaemia. Several studies have demonstrated that dietary supplementation with folic acid and the vitamins B12 and B6 is an efficient means to decrease plasma homocyst(e)ine. No clinical studies are available to date to prove whether reducing homocyst(e)ine levels to the normal range by supplementary B vitamins will also beneficially affect vascular function or cardiovascular risk. Furthermore it is unknown whether moderately elevated homocyst(e)ine concentrations per se may predispose to development of vascular disease, or whether homocyst(e)ine is an indirect marker of cardiovascular disease. Further investigations will be necessary to elucidate the causal relationship between elevated homocyst(e)ine plasma concentrations and the incidence of cardiovascular events, especially since the therapeutic strategies in hyperhomocyst(e)inaemia would differ depending on the underlying pathophysiological mechanisms.

Adult↗

PubMed2001

Endothelial dysfunction in hypertension.

The endothelium can greatly influence vascular tone and structure. The main endothelium-derived factor is nitric oxide (NO), which is not only a potent vasodilator but also inhibits platelet aggregation, smooth muscle cell proliferation, monocyte adhesion and adhesion molecule expression, thus protecting the vessel wall against the development of atherosclerosis and thrombosis. In human hypertension, endothelial dysfunction has been documented in peripheral and coronary macro- and microcirculation and in renal circulation. The mechanism responsible for endothelial alteration in essential hypertensive patients appears to be the activation of an alternative pathway involving cyclooxygenase, which reduces NO availability through production of oxidative stress. In the presence of impaired NO availability a hyperpolarizing factor seems to act as a compensatory pathway to sustain endothelium-dependent relaxation. This compensatory pathway can be further depressed by the simultaneous presence of essential hypertension and hyperhomocysteinaemia, another cardiovascular risk factor causing endothelial dysfunction. Finally, reduced NO availability can increase the biological activity of endothelin-1 because, while in healthy conditions the vasoconstrictor effect of endothelin-1 is partially blunted by endothelial ETB-receptor mediated NO production, in essential hypertensive patients this protective mechanism is lacking on account of impaired NO availability. This alteration in the NO pathway could be the main mechanism through which a dysfunctional endothelium could be a promoter of atherosclerosis and thrombosis and therefore lead to cardiovascular events in essential hypertensive patients.

Biological Factors↗

PubMed2000

[Prospects of endothelial dysfunction reversion in patients with congestive heart failure].

The aim of the study was to investigate the effect of angiotensin-converting enzyme inhibitor enalapril and non-peptide blocker of AT1 receptors losartan on endothelial function of the shoulder artery in patients with congestive cardiac insufficiency. The examination covered 96 patients (mean age 46.71 +/- 4.13) with stable effort angina (functional class II-III) and circulatory insufficiency (NYHA functional class II-III) having end-diastolic left-ventricular volume > 160 ml, left ventricular ejection fraction < 35%, sinus rhythm, cardiothoracal index > 0.55 units. Patients with fibrillar tachyarrhythmia, high grade blocks, pacemaker migration, artificial pacemaker, myocardial infarction were not included in the trial. The patients were randomized into 3 groups 32 patients each. In addition to basic therapy patients of group 1 received long-acting nitrates, digoxin, aspirin and furosemide; group 2--enalapril in daily dose 10 mg; group 3--losartan in daily dose 25 mg. A course of treatment lasted 12 weeks. Endothelial function was assessed by high resolution echography, dopplerography performed before and after temporary occlusion of the shoulder artery and sublingual nitroglycerin. In patients with cardiac insufficiency, accelerated blood flow in the shoulder artery after its temporary occlusion promoted realization of the vasoconstrictory reaction. This was verified as endothelial dysfunction. In the course of the treatment all the patients achieved insignificant increase of the shoulder artery initial diameter. After sublingual intake of nitroglycerin vasodilation was also insignificant. 12-week enalapril and losartan prevented vasoconstriction in the shoulder artery in response to quicker circulation following arterial occlusion. However, higher maximal flow speed did not correspond to the increment in the artery diameter after the occlusion in any group. The flow-induced vasodilation was more pronounced in the enalapril group. Losartan group had a trend to an increase in the inner diameter of the shoulder artery. It is shown that enalapril and losartan in congestive cardiac insufficiency improves endothelium-dependent vasodilation caused by nitroglycerin. Enalapril demonstrated stronger ability than losartan to reverse endothelial dysfunction in patients with cardiac insufficiency resultant from ischemic heart disease.

Angina Pectoris↗

PubMed1999

Cholesterol-independent endothelial dysfunction in virgin and pregnant rats fed a diet high in saturated fat.

1. Western diets high in saturated fat are associated with an increased incidence of cardiovascular diseases. In this study we have evaluated vascular endothelial function and oxidative stress in virgin rats fed a normal (VC) or high in saturated fat diet (VHF) (20 % lard and corn oil w/w) from weaning until adulthood, and throughout subsequent pregnancy (PC and PHF, respectively). 2. The saturated fat diet was associated with enhanced noradrenaline sensitivity in small mesenteric arteries from VHF rats (VHF vs. VC, P < 0.05) and blunted endothelium-dependent relaxation in VHF and PHF rats (VHF vs. VC, P < 0.001; PHF vs. PC, P < 0.05). Endothelial dysfunction was attributable to a reduced nitric oxide component of relaxation in VHF rats, and blunted prostacyclin and endothelium-derived hyperpolarizing factor components in PHF rats. 3. Other than plasma cholesterol, which was reduced in VHF and PHF rats, plasma lipids were normal. Fasting plasma insulin and glucose concentrations were raised in VHF rats (P < 0.05) and the plasma marker of oxidative stress, 8-iso PGF2alpha, was increased in PHF animals (P < 0.01). 4. These findings suggest that endothelial dysfunction induced by a saturated fat diet is cholesterol independent and likely to be of different mechanistic origin in virgin and pregnant rats.

Adipose Tissue↗

PubMed2002

[Endothelial dysfunction in pathogenesis of duodenal ulcer].

It is shown that in patients with ulcer associated with Helicobacter pylori (HP) there is a close correlation between the severity of the lesion of gastroduodenal protective mucous barrier and that of endothelial dysfunction manifesting in elevated level of endothelin-1, serum levels of TBK-active products, inhibition of blood flow and narrowing of the celiac trunk. The correlation becomes stronger with expanding contamination of gastroduodenal mucosa with HP. Thus, HP may participate in breaking the protective mucous barrier in endothelial dysfunction.

Adolescent↗

PubMed1992

Splanchnic vascular endothelial dysfunction in rat endotoxemia: role of superoxide radicals.

Intravenous lipopolysaccharide, 30 mg/kg, results in rapid systemic hypotension in anesthetized rats. Interaction of lipopolysaccharide with the vascular endothelium and blood borne cells results in the elaboration of cytokines and oxygen-derived free radicals, all of which can be injurious to normal endothelial function. To evaluate endothelial function, superior mesenteric artery rings were isolated from endotoxemic rats just prior to death. Endotoxemia significantly blunted superior mesenteric artery ring vasorelaxations to acetylcholine and to A23187 but not to NaNO2. Contraction of superior mesenteric artery rings from endotoxemic rats induced by U46619 was not altered. Treatment with human superoxide dismutase or U74006F, an aminosteroid, significantly preserved vasorelaxation to acetylcholine and A23187. However, the hydroxyl radical scavenger N-(2-mercaptopropionyl)-glycine did not protect the endothelium. Thus, intravenous lipopolysaccharide can induce endothelial dysfunction in superior mesenteric artery rings. Furthermore, because superoxide dismutase but not N-(2-mercaptopropionyl)-glycine preserves endothelial function, it is likely that superoxide radicals mediate the endothelial dysfunction observed in endotoxemic rats.

Acetylcholine↗

PubMed2004

Hydroxy-methylglutaryl-coenzyme A reductase inhibition improves endothelial dysfunction in type-1 diabetes.

OBJECTIVE: We hypothesize that treatment with Pravastatin, a HMG CoA reductase inhibitor would improve flow-mediated dilation (FMD), a nitric oxide dependent phenomenon and the earliest detectable marker of endothelial dysfunction, in asymptomatic patients with type-1 diabetes. MATERIALS AND METHODS: FMD of the brachial artery in response to reactive hyperaemia was measured using high-resolution ultrasonography. Young male patients with type-1 diabetes (n=9) were compared with age matched non-diabetic controls (n=8). RESULTS: The FMD response in the control group was a median increase in diameter of 7.9 (range 3.8-12.6)%. In the diabetic group the FMD response was impaired when compared with controls with a median increase only of 4.4 (range 3.7-5.8)% (p<0.01). Following Pravastatin, 40 mg per day for one month in the diabetic group, there was a significant diameter change in response to reactive hyperaemia with a median of 8.4 (range 6.9-12.6)% (p<0.01). CONCLUSIONS: These data confirm the presence of endothelial dysfunction in young patients with type-1 diabetes. We have shown that 1-month of Pravastatin treatment normalizes FMD. This suggests that HMG CoA reductase inhibitors may have a role in the management of diabetes mellitus, even in the presence of normal serum cholesterol levels.

Adolescent↗

PubMed1995

Soluble adhesion molecule P-selectin and endothelial dysfunction in essential hypertension: implications for atherogenesis? A preliminary report.

OBJECTIVE: Patients with essential hypertension are at high risk of atherosclerotic vascular disease. To investigate this further, we measured levels of the soluble adhesion molecule P-selectin, which is associated with platelet activity/function and atherosclerosis, von Willebrand factor, which is a marker of endothelial dysfunction, and plasma fibrinogen. PATIENTS AND METHODS: We studied 104 consecutive patients (47 males, 57 females; mean +/- SD age 54.8 +/- 14.1 years) with essential hypertension compared with 47 normotensive healthy controls (55.0 +/- 19.2 years). Levels of soluble adhesion molecule P-selectin and von Willebrand factor were measured by enzyme-linked immunosorbent assay, and plasma fibrinogen by a clotting method (CLAUSS). RESULTS: Compared with normotensives, the hypertensives showed significant increases in soluble P-selectin (300 versus 228 ng/ml; median difference 55 ng/ml, Mann-Whitney test P = 0.03), von Willebrand factor (114 versus 96 IU/I; unpaired t-test P < or = 0.001) and fibrinogen (3.3 versus 2.9 g/l; unpaired t-test P < or = 0.001). There were significant correlations between fibrinogen and P-selectin (r = 0.16; P = 0.02) and von Willebrand factor (r = 0.39; P<0.001), but not between P-selectin and von Willebrand factor. There were no differences in these factors between patients with (n = 53) and without (n = 51) antihypertensive therapy or between those with good blood pressure control (systolic/diastolic < or = 160/90 mmHg; n = 17) and those with poor control. A stepwise multiple regression analysis showed that diastolic blood pressure was a significant predictor for soluble P-selectin levels; diastolic blood pressure and von Willebrand factor levels were significant predictors for fibrinogen levels (P<0.05). CONCLUSIONS: This study suggests that hypertensives have high plasma fibrinogen levels, platelet dysfunction (which could contribute to atherogenesis, as indicated by raised soluble P-selectin levels) and endothelial dysfunction (as indicated by high von Willebrand factor levels), which are related to diastolic blood pressure. These factors may act synergistically to increase atherogenesis and may explain the high risk of atherosclerotic vascular disease in hypertensives.

Arteriosclerosis↗

PubMed2005

Combination therapy with cerivastatin and nifedipine improves endothelial dysfunction after balloon injury in porcine coronary arteries.

HMG-CoA reductase inhibitors and calcium channel blockers have antiatherogenic effects; however, their mechanisms remain to be elucidated. This study examined the effect of cerivastatin and/or nifedipine on the endothelial dysfunction in porcine balloon-injured coronary arteries. Normal male pigs were randomly divided into the following four groups: control, cerivastatin (1 mg/kg/d PO), nifedipine (4 mg/kg/d PO), and their combination (n = 10 each). We started the treatments 3 days before balloon injury in the proximal left coronary arteries and continued for 4 weeks after the procedure. Then, we examined endothelial vasodilator functions ex vivo in organ chambers and in vitro by Western blotting for eNOS expression. Endothelium-dependent relaxations to serotonin, but not those to bradykinin or the calcium ionophore A23187 or endothelium-independent relaxations to sodium nitroprusside, were significantly impaired by balloon injury. The monotherapy with cerivastatin or nifedipine partially improved, and their combination supernormalized the relaxations to serotonin without affecting those to bradykinin or A23187 or endothelium-independent relaxations to sodium nitroprusside. The expression of eNOS was significantly reduced by balloon injury and normalized by the combination therapy. These results indicate that the combination therapy improves endothelial dysfunction after balloon injury, in which the up-regulation of eNOS may be involved.

Administration, Oral↗

PubMed2004

The post-prandial state in Type 2 diabetes and endothelial dysfunction: effects of insulin aspart.

OBJECTIVE: Recently, much attention has been focused on the possibility that the post-prandial state may be a cardiovascular risk factor in diabetes. The aim of the present study was to evaluate whether the post-prandial state is associated with endothelial dysfunction in patients with diabetes and to explore the effect on this aspect of managing post-prandial hyperglycaemia by insulin aspart. RESEARCH DESIGN AND METHODS: Twenty-three patients with Type 2 diabetes and 10 normal controls were recruited. In the diabetic patients two different tests were performed in each subject: a standard meal preceded by subcutaneous injection of soluble insulin (0.15 U/kg body weight) or of short-acting insulin aspart (0.15 U/kg body weight). These tests were designed to achieve different levels of post-prandial hyperglycaemia. Controls received a single standard meal test. Immediately before, and 1, 2, 4 and 6 h after each meal, blood glucose, triglycerides, free fatty acids and flow-mediated vasodilation were measured. RESULTS: Compared with regular insulin, insulin aspart significantly reduced the area under the curve for post-prandial hyperglycaemia (58.3 +/- 17.6 vs. 68.1 +/- 17.7; P<0.04), and preserved flow-mediated vasodilation, which was decreased in the post-prandial state (39.4 +/- 2.9 vs. 34.1 +/- 2.2; P<0.01). Triglyceride and free fatty acid levels were not differentially affected by the treatment. In normal controls the meal did not affect flow-mediated vasodilation. CONCLUSION: This study shows that the post-prandial state is accompanied by endothelial dysfunction in Type 2 diabetic patients and that insulin aspart improved endothelial function.

Diabetes Mellitus, Type 2↗

PubMed1999

Arterial endothelial dysfunction related to passive smoking is potentially reversible in healthy young adults.

BACKGROUND: Passive smoking is associated with early arterial damage, but the potential for reversibility of this damage is unknown. OBJECTIVE: To assess the reversibility of arterial endothelial dysfunction, a key marker of early atherosclerosis. DESIGN: Cross-sectional study. SETTING: Academic medical center. PARTICIPANTS: 60 healthy persons 15 to 39 years of age: 20 with no exposure to active or passive smoking, 20 nonsmoking passive smokers (exposure to environmental tobacco smoke for > or = 1 hour per day for > or = 2 years), and 20 former passive smokers. MEASUREMENTS: Arterial endothelial function measured by noninvasive ultrasonography. RESULTS: Endothelium-dependent dilatation was significantly better in former passive smokers (5.1% +/- 4.1% [range, -1.2% to 15.6%]) than in current passive smokers (2.3% +/- 2.1% [range, -0.2% to 6.7%]) (P = 0.01), although both groups were significantly impaired compared with nonsmoking controls (8.9% +/- 3.2% [range, 2.1% to 16.7%]) (P < or = 0.01 for both comparisons). CONCLUSIONS: In healthy young adults, arterial endothelial dysfunction related to passive smoking seems to be partially reversible.

Adolescent↗

PubMed2001

The phytoestrogen alpha-zearalenol reverses endothelial dysfunction induced by oophorectomy in rats.

It has been shown recently that alpha-zearalenol, a resorcyclic acid lactone, prevents bone loss in a rat model of postmenopausal bone loss. We have therefore investigated the effects of this phytoestrogen on endothelial dysfunction induced by estrogen deficiency in rats. Female mature Sprague-Dawley rats underwent a bilateral oophorectomy (OVX rats). Sham-operated animals (sham OVX rats) were used as controls. Three weeks after surgery, animals were randomized to the following treatments: alpha-zearalenol (1 mg/kg/day, i.m., for 4 weeks), 17beta-estradiol (20 microg/kg/day, i.m., for 4 weeks), or their vehicle (100 microl, i.m., of cottonseed oil). Two other groups of rats were treated with alpha-zearalenol or 17beta-estradiol plus the pure estrogen receptor antagonist ICI 182780 (2.5 mg/kg/day, i.m., for 4 weeks). Mean arterial blood pressure (MAP), heart rate (HR), total plasma cholesterol, plasma estradiol, and plasma alpha-zearalenol were studied. We also investigated endothelial-dependent (acetylcholine, 10 nM to 10 microM) and endothelial-independent (sodium nitroprusside, 15 nM to 30 nM) relaxation of aortic rings, as well as N(G)-methyl-L-arginine (L-NMA: 10 to 100 microM)-induced vasoconstriction and calcium-dependent nitric oxide synthase (cNOS) activity in homogenates of lungs taken from both sham OVX rats and OVX rats. Untreated OVX rats had, compared with sham OVX animals, unchanged body weight, MAP, HR, and plasma cholesterol. In contrast oophorectomy reduced plasma estradiol levels (OVX, 2 +/- 0.5 pg/ml; sham OVX, 35 +/- 6 pg/ml), impaired endothelial-dependent relaxation and blunted L-NMA-induced contraction (L-NMA 100 microM: sham OVX, 2.7 +/- 0.3 g/mg tissue; OVX, 1.3 +/- 0.1 g/mg tissue). Moreover OVX rats showed a reduced calcium-dependent NO synthase (cNOS) activity. Treatment with alpha-zearalenol or with 17beta-estradiol reverted the endothelial dysfunction and increased cNOS activity in lung homogenates. These effects were abolished by the pure estrogen receptor antagonist ICI 182780. Our data suggest that alpha-zearalenol improves endothelial-dependent relaxation in OVX rats through an estrogen receptor-mediated effect.

Acetylcholine↗

PubMed2000

A possible link between endothelial dysfunction and insulin resistance in hypertension. A LIFE substudy. Losartan Intervention For Endpoint-Reduction in Hypertension.

BACKGROUND: We wanted to investigate whether insulin resistance and time to steady state during isoglycemic clamp were associated with endothelial dysfunction, peripheral vascular remodeling and forearm blood flow (FBF) in patients with longstanding hypertension. METHODS: In 43 unmedicated, hypertensive patients with electrocardiographic-defined left ventricular hypertrophy we performed a 2-h oral glucose tolerance test and a 3-h isoglycemic hyperinsulinemic clamp with measurements of circulating plasma epinephrine and FBF by plethysmography. Delayed steady state was assessed by measuring the increase in insulin sensitivity from the second to the third hour of clamping. We measured 24-h ambulatory blood pressure, minimal forearm vascular resistance (MFVR) by plethysmography, media:lumen ratio (MLR) and acetylcholine-induced relaxation (AIR) in isolated, subcutaneous resistance arteries by myography. RESULTS: Insulin sensitivity after 2 and 3 h of clamping was not related to maximal AIR, MLR, MFVR or FBF. The increase in insulin sensitivity in men was negatively correlated to maximal AIR (r = -0.36, p < 0.05), and was independently correlated to relative changes in FBF (beta = 0.46) and in circulating epinephrine (beta = 0.33; adj. R = 0.33, p < 0.001). CONCLUSIONS: Insulin sensitivity was not correlated to parameters of peripheral vascular remodeling, endothelial function or microvascular rarefaction in patients with longstanding hypertension and left ventricular hypertrophy. However, the action of insulin on peripheral glucose uptake was influenced by endothelial dysfunction (delayed transcapillary insulin transport) and by changes in and/or redistribution of blood flow suggesting a link between vascular function and insulin sensitivity.

Aged↗

PubMed1999

Vascular endothelial growth factor attenuates leukocyte-endothelium interaction during acute endothelial dysfunction: essential role of endothelium-derived nitric oxide.

Vascular endothelial growth factor (VEGF) is an endothelium-specific secreted protein that induces vasodilation and increases endothelial release of nitric oxide (NO). NO is also reported to modulate leukocyte-endothelium interaction. Therefore, we hypothesized that VEGF might inhibit leukocyte-endothelium interaction via increased release of NO from the vascular endothelium. We used intravital microscopy of the rat mesenteric microcirculation to measure leukocyte-endothelium interactions 2, 4, and 24 h after systemic administration of VEGF to the rat (120 microg/kg, i.v., bolus). Superfusion of the rat mesentery with either 0.5 U/ml thrombin or 50 microM L-NAME consistently increased the number of rolling, adhering, and transmigrated leukocytes (P<0.01 vs. control mesenteries superfused with Krebs-Henseleit buffer). At 4 and 24 h posttreatment, VEGF significantly attenuated thrombin-induced and L-NAME-induced leukocyte rolling, adherence, and transmigration in rat mesenteric venules. In addition, adherence of isolated rat PMNs to thrombin-stimulated mesenteric artery segments in vitro was significantly reduced in mesenteric arteries isolated from VEGF-treated rats (P<0.001 vs. control rats). Direct measurement of NO demonstrated a threefold increase in basal NO release from aortic tissue of rats injected with VEGF, at 4 and 24 h posttreatment (P<0. 01 vs. aortic tissue from control rats). Finally, systemic administration of VEGF to ecNOS-deficient mice failed to inhibit leukocyte-endothelium interactions observed in peri-intestinal venules. We concluded that VEGF is a potent inhibitor of leukocyte-endothelium interaction, and this effect is specifically correlated to augmentation of NO release from the vascular endothelium.--Scalia, R., Booth, G., Lefer, D. J. Vascular endothelial growth factor attenuates leukocyte-endothelium interaction during acute endothelial dysfunction: essential role of endothelium-derived nitric oxide.

Animals↗

PubMed1989

Endothelial dysfunction and atherosclerosis.

There is increasing evidence that the vascular endothelium is an important functional component of the blood vessel wall, actively participating in normal vascular physiology as well as the pathogenesis of vascular diseases such as atherosclerosis. The localized modulation of vascular endothelium to a nonadaptive functional state can be termed endothelial dysfunction. This article provides a brief overview of the multiple vital functions of endothelium, and a working concept of endothelial dysfunction especially as it relates to atherosclerosis and its thrombotic complications.

Arteriosclerosis↗

PubMed1998

The atherogenic lipoprotein phenotype and vascular endothelial dysfunction.

There is accumulating evidence that elevated plasma triglycerides and related abnormalities constitute an independent cardiovascular risk factor. Although the pathogenetic basis for the apparent relationship between elevated triglyceride-rich lipoproteins and CAD is still uncertain, evidence is accumulating to suggest that endothelial dysfunction is involved. There is evidence to suggest that triglyceride-rich particles may be directly damaging to the endothelium; this may be principally via oxidative mechanisms. Triglyceride-rich particles can cross the endothelial barrier and enter the arterial wall, thus placing them in a position to promote direct endothelial damage. These particles stimulate endothelial expression of adhesion molecules and the prothrombotic factor PAI-1. By reducing LDL size and HDL cholesterol concentrations, thereby further increasing the endothelial oxidative burden, triglyceride-rich particles may indirectly promote endothelial dysfunction. In addition, free fatty acids, which are the major substrates for endogenous synthesis of triglyceride-rich particles, are also potentially damaging to the endothelium. This occurs via oxidative stress, by facilitating transfer of LDL across the endothelium, and by enhancing toxicity of triglyceride-rich particles. Finally, there is recent strong evidence to suggest that increased postprandial circulating concentrations of triglyceride-rich particles and remnant particles may be deleterious to the endothelium.

Animals↗