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Clinical importance of endothelial function in arteriosclerosis and ischemic heart disease.

The vascular endothelium is a dynamic endocrine organ that regulates vascular tone, local homeostasis, and the fibro-inflammatory-proliferative process. These responses are mediated by various substances released from the endothelium in response to physiologic stimuli, including prostacyclin, endothelin and, most importantly, nitric oxide (NO). NO mediates vasodilation and inhibits platelet aggregation, thrombus formation, expression of adhesion molecules and chemokines for leukocytes, and oxidative stress. It also attenuates growth and proliferation of vascular smooth muscle cells. Risk factors for atherosclerosis, such as hypercholesterolemia, hypertension, diabetes and cigarette smoking, impair endothelial function, which leads to atherosclerosis and results in ischemic manifestations such as acute coronary syndrome and stroke. Thus, therapeutic intervention aimed at increasing NO bioavailability by statins or angiotensin-converting enzyme inhibitors might improve patient prognosis. Vascular endothelial function is an important and clinically relevant therapeutic target for cardiovascular disease.

Arteriosclerosis↗

Does oral folic acid lower total homocysteine levels and improve endothelial function in children with chronic renal failure?

BACKGROUND: Accelerated vascular disease is common in chronic renal failure (CRF) and accounts for significant mortality and morbidity. Elevated homocysteine levels may contribute by an effect on endothelial function. METHODS AND RESULTS: We performed a double-blind placebo-controlled randomized crossover trial of folic acid at 5 mg/m2 in 25 normotensive children 12+/-3 (7 to 17) years of age with CRF (glomerular filtration rate 26.8+/-13.2 mL/min per 1.73 m2) of noninflammatory etiology. Each subject underwent two 8-week periods of folic acid and placebo separated by an 8-week washout period. The effect of folic acid on homocysteine levels, LDL oxidation, and both endothelial-dependent and -independent vascular function were measured. After oral folic acid, serum folate levels rose from 11.7+/-4.25 to 635+/-519 microg/L (P=0.001), red cell folate levels rose from 364+/-195 to 2891+/-2623 microg/L (P<0.001), and total homocysteine levels fell from 10.28+/-4.16 to 8.62+/-2.32 micromol/L (P=0.03). In addition, there was a significant improvement in flow-mediated dilatation (FMD) (endothelial-dependent dilatation) from 7.21+/-2.8% to 8.47+/-3.01% (P=0.036) with no change in response to glyceryl trinitrate (endothelial-independent dilatation). There was no significant change in FMD or glyceryl trinitrate during the placebo phase. There was, however, no significant difference in final FMD after placebo or folic acid. Lag times for LDL oxidation were prolonged during the treatment phase (58.4+/-18.7 to 68.1+/-25.9 minutes, P=0.01). CONCLUSION: Folic acid supplementation in children with CRF may improve endothelial function with an increased resistance of LDL to oxidation.

Administration, Oral↗

Gene transfer of extracellular superoxide dismutase improves endothelial function in rats with heart failure.

Oxidative stress is associated with endothelial dysfunction in heart failure. The goals of this study were to determine whether 1) gene transfer of extracellular superoxide dismutase (ecSOD) reduces levels of superoxide and improves endothelial function in the aorta and mesenteric artery in rats with heart failure, and 2) the heparin-binding domain (HBD) of ecSOD, by which ecSOD binds to cells, is required for protective effects of ecSOD. Seven weeks after coronary ligation, in rats with heart failure and sham-operated rats, we injected adenoviral vectors intravenously that express ecSOD, ecSOD with deletion of the HBD (ecSODDeltaHBD), or a control vector. Four days after injection of viruses, responses to acetylcholine, ADP, and sodium nitroprusside were examined in rings of the aorta and mesenteric artery. ecSOD bound to endothelium and increased SOD activity in the aorta after gene transfer of ecSOD, not ecSODDeltaHBD. Gene transfer of ecSOD, but not ecSODDeltaHBD, reduced levels of superoxide and improved relaxation to acetylcholine and ADP in the aorta and mesenteric artery from rats with heart failure. Improvement of relaxation to acetylcholine in the mesenteric artery from rats with heart failure after gene transfer of ecSOD was mediated in part by hydrogen peroxide. The major finding of this study is that the HBD of ecSOD is necessary for protection against endothelial dysfunction in rats with heart failure. We speculate that a common gene variant in the HBD of ecSOD, which is a risk factor for ischemic heart disease, may be a risk factor for vascular maladaptation and endothelial dysfunction in heart failure.

Animals↗

Disruption of the rat mesenteric arterial bed endothelial function by air perfusion.

The impact of air perfusion on the endothelial function of the rat mesenteric arterial bed (MAB; perfused with Krebs' bicarbonate plus indomethacin) was compared to that of the NO synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME). Air shifted the dose-response curve for the alpha-adrenoceptor agonist, norepinephrine (NE) to the left (ED50%: 2.9+/-0.7 to 0.9+/-0.7 microg, P < 0.05); maximal vasoconstriction did not change. L-NAME produced a similar increase in midrange sensitivity (ED50% 1.4+/-0.7 microg, P < 0.05) and a 20% increase in maximum (152+/-6 to 183+/-7 mmHg, P < 0.05). Electromechanical stimulation with potassium chloride (KCl) was not modified by reserpine. Neither air nor L-NAME modified midrange sensitivity to KCl. L-NAME produced a 17% increase in maximum (91+/-4 to 107+/-5 mmHg, P < 0.05); reserpine abolished the latter effect. Air and L-NAME diminished endothelium-dependent vasodilation elicited by carbachol. Air did not modify endothelium-dependent vasodilation elicited by sodium nitroprusside; this response was potentiated by L-NAME. In summary, air and L-NAME produced similar effects on receptor-dependent activation of the endothelial L-arginine nitric oxide (NO) pathway. Potentiation by L-NAME of the maximal electromechanical response suggests the existence of a tone-dependent NO system. Abolition of the latter response by reserpine suggests that this system is of sympathetic origin.

Air↗

[Determination of endothelial function in children with nephrotic syndrome in various states of disease].

Endothelial function in clinical condition can be estimated non-invasively in peripheral circulation with high-resolution ultrasound imaging of flow-mediated dilation (FMD) of brachial artery. The aim of the report is the estimation of FMD in children with nephrotic syndrome (NS) in various states of disease. Forty one children with primary NS (22 boys and 19 girls) aged 9-20,3 years (mean age 15,4 years) were examined. The patients were divided into two groups. Group I (24 children) consisted of children in remission of steroid-dependent or steroid-resistant NS in course of Cyclosporin A treatment. Group II consisted of 17 patients admitted to our Clinical Department with relapse of NS. FMD examination was performed in both groups and proportional change in brachial artery diameter before and after four minutes long ischaemia caused by sphygmomanometer cuff pressure was estimated. As a norm 6% of extension was adopted. Mean FMD in group I was 7,2+/-7,4% and in group 11: 5,9+/-5,4% (p=NS). 63% patients in group I and 53% in group II had the results below normal values. Endothelial dysfunction can be observed in children with nephrotic syndrome. Endothelial dysfunction is presented both in relapse of disease and in children treated with Cyclosporin A.

Adolescent↗

Relationship between S-adenosylmethionine, S-adenosylhomocysteine, asymmetric dimethylarginine, and endothelial function in healthy human subjects during experimental hyper- and hypohomocysteinemia.

Experimental hyperhomocysteinemia after an oral methionine or homocysteine load is associated with impaired nitric oxide-dependent vasodilatation in healthy human beings. However, it remains unproven that this effect is mediated by elevations in plasma homocysteine. There is evidence that an increase in plasma homocysteine may increase the formation of asymmetric dimethylarginine (ADMA), an inhibitor of nitric oxide synthase. The methyl groups within ADMA are derived from the conversion of S -adenosylmethionine to S -adenosylhomocysteine intermediates in the methionine/homocysteine pathway. No previous study has assessed the role of methylation status, its impact on ADMA formation, and their association with endothelial function in healthy human beings. In a randomized, placebo-controlled, crossover study, 10 healthy subjects (mean age, 29.1 +/- 3.9 years) were administered an oral dose of methionine (0.1 g/kg), l -homocysteine (0.01 g/kg), N-acetylcysteine (NAC) (0.1 g/kg), or placebo. Endothelial function as assessed by flow-mediated dilatation (FMD) of the brachial artery was impaired after both the methionine and homocysteine load compared with placebo at 4 hours (36 +/- 15, 67 +/- 23 vs 219 +/- 26 microm, respectively, P < .001). N-Acetylcysteine had no effect on flow-mediated dilatation. Plasma total homocysteine was significantly elevated at 4 hours after methionine (23.1 +/- 6.2) and homocysteine (41.5 +/- 8.9) loading, but significantly reduced after NAC 2.4 +/- 0.6 vs 7.1 +/- 2.1 micromol/L in the placebo (P < .001). Plasma S-adenosylmethionine/S-adenosylhomocysteine ratio was significantly (P < .001) increased at 4 hours after methionine (10.9 +/- 0.7) compared with homocysteine (5.4 +/- 0.4), NAC (5.0 +/- 0.3), and placebo (6.0 +/- 0.5). Plasma ADMA concentrations were not altered by any intervention. Our results suggest that endothelial dysfunction due to methionine or homocysteine loading is not associated with an increase in plasma ADMA or a disruption in methylation status.

Acetylcysteine↗

Impaired endothelial function of the umbilical artery after fetal cardiac bypass.

BACKGROUND: Recently, endothelial dysfunction as a result of fetal cardiac bypass has been reported. Here, the effect of fetal cardiac bypass on the endothelial function of the umbilical artery was investigated by a tension study. METHODS: Fourteen fetal lambs were divided into a control group (n = 7) and a pump group (n = 7). In the pump group, cardiac bypass was maintained for 30 minutes using a low-volume priming circuit with a centrifugal pump. Hemodynamic measurements and blood gas analyses were performed before, during, and 30 and 60 minutes after cardiac bypass. The umbilical artery was harvested 60 minutes after cessation of cardiac bypass. Endothelium-dependent relaxation (bradykinin, calcium ionophore A23187) and endothelium-independent relaxation (sodium nitroprusside) were measured after smooth muscle contraction by 60 mmol/L potassium or serotonin and compared between the two groups. RESULTS: The umbilical artery flow and aortic pressure of the fetus were significantly decreased at 30 and 60 minutes after cardiac bypass. Hypoxia and hypercapnia were recognized during and after cardiac bypass. Metabolic acidosis progressed during and after cardiac bypass. Endothelium-dependent relaxation was impaired in the pump group compared with the control group (bradykinin: 43.6% +/- 6.4% in the control group, 18.9% +/- 2.5% in the pump group, p < 0.01; A23187: 37.8% +/- 4.6% in the control group, 19.6% +/- 3.9% in the pump group, p < 0.01). Meanwhile, endothelium-independent relaxation was preserved in both groups. CONCLUSIONS: Fetal cardiac bypass caused endothelial dysfunction of the umbilical artery and hemodynamic deterioration as a result of metabolic acidosis. Prevention of endothelial damage and metabolic acidosis could be the main target for successful fetal cardiac surgery.

Animals↗

The effect of acute exercise on endothelial function following a high-fat meal.

The transient impairment of endothelial function following a high-fat meal is well established. Brachial artery flow-mediated dilation (FMD) decreases between 2 and 6 h post ingestion. Whether this impairment can be reduced with acute aerobic exercise has not been investigated. The purpose of this study was to investigate if a single sustained aerobic exercise session can counteract the postprandial attenuation in brachial artery FMD associated with the ingestion of a high-fat meal. Eight apparently healthy adults (five men, three women), age 25.5 +/- 0.8 years, performed three treatment conditions in a counter-balanced design: (1) low-fat meal alone (LFM), (2) high-fat meal alone (HFM), and (3) one session of aerobic exercise presented 2 h after ingesting a high-fat meal (HFM-EX). The examination of brachial artery FMD was performed at baseline and 4 h following the ingestion of the meal for each treatment condition. A 3 x 2 (treatment x time) repeated measures ANOVA exhibited a significant interaction (P = 0.019). Preprandial FMDs were similar (P = 0.863) among all three treatment conditions. The FMDs following the LFM (7.18 +/- 1.31%) and HFM-EX (8.72 +/- 0.94%) were significantly higher (P = 0.001) than the FMD following the HFM (4.29 +/- 1.64%). FMD was significantly elevated above preprandial values following the HFM-EX (5.61 +/- 1.54 to 8.72 +/- 0.94%, P = 0.005) but was unchanged following the LFM (6.17 +/- 0.94 to 7.18 +/- 1.31%, P = 0.317) and the HFM (5.73 +/- 1.23 to 4.29 +/- 1.64%, P = 0.160). These findings suggest that a single aerobic exercise session cannot only counteract the postprandial endothelial dysfunction induced by the ingestion of a high-fat meal, but also increase brachial artery FMD in apparently healthy adults.

Adult↗

Glutathione-S-transferase genotypes, smoking, and their association with markers of inflammation, hemostasis, and endothelial function: the atherosclerosis risk in communities (ARIC) study.

Recent epidemiologic studies suggest that polymorphisms of glutathione-S-transferases M1 and T1 (GSTM1/GSTT1) modify the effects of cigarette smoking on risk of coronary heart disease (CHD). Since GSTs are able to detoxify numerous toxic compounds and products of oxidative stress, it is possible that GST genotypes may also modify the capacity of smoking to invoke a chronic inflammatory response. A cross-sectional analysis, using a subset of participants (n = 989) in a large (n = 15, 792) biracial cohort, was used to evaluate levels of nine markers of inflammation, hemostasis, and endothelial function by different combinations of GST genotypes and cigarette smoking status. Participants with the GSTM1 null (GSTM1-0) genotype and > or = 20 pack-years of smoking had the highest mean levels of CRP, fibrinogen, von Willebrand factor, ICAM-1, and VCAM-1 and lowest mean levels of albumin compared to other combinations of genotype and smoking. However, a formal test for interaction between GSTM1 genotype and smoking was statistically significant only for albumin. By contrast, participants who had the functional GSTT1 genotype (GSTT1-1) and smoked > or = 20 pack-years had the highest mean levels of only CRP and fibrinogen. The results of this study provide some limited evidence that GSTM1 and GSTT1 polymorphisms modify the effect of smoking on inflammation, hemostasis, and endothelial function.

Cohort Studies↗

Rapid restoration of normal endothelial functions in genetically hyperlipidemic mice by a synthetic mediator of reverse lipid transport.

Endothelial dysfunction is a major pathophysiological consequence of hypercholesterolemia and other conditions. We examined whether a synthetic mediator of lipid transport from peripheral tissues to the liver (ie, the "reverse" pathway) could restore normal endothelial function in vivo. Using assays of macrovascular and microvascular function, we found that genetically hypercholesterolemic apolipoprotein E knockout mice exhibited key endothelial impairments. Treatment of the mice for 1 week with daily intravenous bolus injections of large "empty" phospholipid vesicles, which accelerate the reverse pathway in vivo, restored endothelium-dependent relaxation, leukocyte adherence, and endothelial expression of vascular cell adhesion molecule-1 to normal or nearly normal levels. These changes occurred despite the long-standing hyperlipidemia of the animals and the persistence of high serum concentrations of cholesterol-rich atherogenic lipoproteins during the treatment. Our results indicate that dysfunctional macrovascular and microvascular endothelium in apolipoprotein E knockout mice can recover relatively quickly in vivo and that accelerated reverse lipid transport may be a useful therapy.

Animals↗

Lipid profiles and endothelial function with low-dose hormone replacement therapy in postmenopausal women at risk for coronary artery disease: a randomized trial.

AIMS: To compare the effect of low (0.3 mg) and commonly prescribed (0.625 mg) doses of conjugated equine estrogens (CEE) on brachial artery flow-mediated dilation and lipid profiles. METHODS AND RESULTS: Twenty-five postmenopausal women (mean age, 65+/-6 years) at risk for coronary artery disease (CAD) (> or =2 established risk factors) entered a double-blind crossover study. Brachial artery endothelial function was evaluated by means of high-resolution vascular echography. Both CEE doses significantly decreased total cholesterol (-13%, 0.3 mg; -15%, 0.625 mg), low-density lipoprotein-cholesterol (LDL-C) (-15%, 0.3 mg; -16%, 0.625 mg), and lipoprotein(a) (-28%, 0.3 mg; -39%, 0.625 mg) values from baseline levels. Both treatments increased high-density lipoprotein-cholesterol (HDL-C) (5%, 0.3 mg; 7%, 0.625 mg) and triglycerides (3%, 0.3 mg; 8%, 0.625 mg). There was no dose effect for changes in the LDL-C/HDL-C ratio (-21%, 0.3 mg; -23%, 0.625 mg). Both doses improved brachial artery dilation during reactive hyperemia by 63% over baseline. CONCLUSION: In women at risk for CAD, low-dose hormone replacement treatment (HRT) improves lipid profiles and brachial artery endothelial function comparably to the most commonly prescribed dose. The benefit:risk ratio of low-dose HRT provides an attractive option for postmenopausal women at risk for CAD.

Aged↗

Insulin therapy improves endothelial function in type 2 diabetes.

A total of 75 in vivo endothelial function tests (intrabrachial artery infusions of endothelium-dependent [acetylcholine] and -independent [sodium nitroprusside] vasoactive agents) were performed in 18 type 2 diabetic patients (aged 58+/-2 years, body mass index 28.5+/-0.6 kg/m(2), and fasting plasma glucose 229+/-11 mg/dL) and 27 matched normal subjects. These tests were performed before and 6 months after combination therapy with insulin and metformin and before and 6 months after metformin therapy only. Before insulin therapy, blood flow responses to acetylcholine (15 microg/min) were significantly blunted in type 2 diabetic patients (7.5+/-0.7 mL x dL(-1) x min(-1)) compared with normal subjects (11.6+/-0.9 mL x dL(-1) x min(-1), P<0.01). During insulin therapy, the acetylcholine response increased by 44% to 10.8+/-1.6 mL x dL(-1) x min(-1) (P<0.05). Insulin therapy also significantly increased the blood flow responses to both low and high doses of sodium nitroprusside. We conclude that insulin therapy improves endothelium-dependent and -independent vasodilatation. These data support the idea that insulin therapy has beneficial rather than harmful effects on vascular function.

Blood Glucose↗

Glucocorticoids inhibit tetrahydrobiopterin-dependent endothelial function.

Tetrahydrobiopterin (BH4) acts as an important co-factor for endothelial nitric oxide synthase (eNOS). Glucocorticoids have been shown to inhibit expression of the rate-limiting enzyme for tetrahydrobiopterin synthesis, GTP cyclohydrolase, in other cell types. We hypothesized that endothelium-dependent vasodilator responses would be blunted in rats made hypertensive with dexamethasone. Further, we hypothesized that treatment of rat vascular segments with dexamethasone would result in attenuation of endothelial function accompanied by decreased GTP cyclohydrolase expression. We report that endothelium-dependent relaxation responses to the calcium ionophore A23187 are reduced in aortic rings from dexamethasone-hypertensive rats compared with sham values. Dexamethasone incubation abolishes contraction to Nomega-nitro-L-arginine (L-NNA, 10(-5) M) in endothelium-intact aortic rings, and inhibits expression of GTP cyclohydrolase. We conclude that inhibition of BH4 synthesis by glucocorticoid regulation of GTP cyclohydrolase expression may contribute to reduced endothelium-dependent vasodilation characteristic of glucocorticoid-induced hypertension.

Animals↗

Protection of aortic endothelial function in both normal and diabetic rats by intravenous bolus injection of a medium-chain triglyceride: fish oil emulsion.

The bolus intravenous injection of a novel medium-chain triglyceride:fish oil emulsion (MCT:FO) was recently proposed as a tool to provoke a rapid and sustained increase of cell phospholipid content in long-chain polyunsaturated omega3 fatty acids, for instance in selected subjects prior to anesthesia and surgery. In this study, therefore, the possible protective effect of MCT:FO upon aortic endothelial function was investigated in both normal and diabetic rats. The animals were injected intravenously 20 h before sacrifice with 1.0 ml of either saline, MCT:FO or a control medium-chain triglyceride:long-chain triglyceride emulsion. The vasomotor response of isolated aortic rings was then explored by assessing the relaxation provoked by increasing concentrations of acetylcholine in rings contracted with phenylephrine. Such measurements were performed before and after exposure of the aortic rings to suitable concentrations of oxidized LDL. In both normal and diabetic rats, the prior injection of the MCT:FO emulsion protected the aortic rings against the deleterious effect of oxidized LDL. In the diabetic rats, a beneficial effect of the MCT:FO emulsion was even observed prior to exposure of the aortic rings to oxidized LDL. These findings support the view that this novel procedure is indeed appropriate to protect endothelial function against oxidative stress.

Acetylcholine↗

Heat stress-induced protection of endothelial function against ischaemic injury is abolished by ATP-sensitive potassium channel blockade in the isolated rat heart.

The protection conferred by heat stress (HS) against myocardial ischaemia-reperfusion injury, in terms of mechanical function preservation and infarct size reduction, is well documented and mechanisms underlying these effects have been extensively explored. However, the effect of HS on coronary circulation is less known. The aim of this study was thus to investigate the role of ATP-sensitive potassium (K(ATP)) channels in the protection against ischaemic injury afforded by HS to the coronary endothelial function. Twenty-four hours after whole body hyperthermia (42 degrees C for 15 min, H groups) or sham anaesthesia (Sham groups), isolated perfused rat hearts were subjected to a 15 min stabilization period followed by a 30 min infusion of either 0.3 microM glibenclamide (Gli, a K(ATP) channel blocker) or its vehicle (V). Hearts were then exposed to a low-flow ischaemia (30 min)-reperfusion (20 min) (I/R) or normally perfused (50 min), after which coronaries were precontracted with 0.1 microM U-46619. Finally, the response to the endothelium-dependent vasodilator, 5-hydroxytryptamine (5-HT, 10 microM) was compared to that of the endothelium-independent vasodilator, sodium nitroprusside (SNP, 3 microM). In hearts from Sham-V and Sham-Gli groups, I/R selectively diminished 5-HT-induced vasodilatation without affecting the vasodilatation to SNP. In V-treated groups, prior HS preserved the vasodilatation produced by 5-HT. This HS-induced protection was abolished by Gli treatment. In conclusion, these results suggest that K(ATP) channel activation contributes to the preservation of coronary endothelial function conferred by heat stress against ischaemic insult.

ATP-Binding Cassette Transporters↗

Endothelin and von Willebrand factor as parameters of endothelial function in idiopathic dilated cardiomyopathy: different stimuli for release before and after heart transplantation?

BACKGROUND: Congestive heart failure (CHF) and heart transplantation (HTX) are characterized by endothelial dysfunction as indicated by elevation of markers of endothelial function, including endothelin and von Willebrand factor (vWF). However, previous studies included both patients with idiopathic dilated cardiomyopathy and ischemic heart disease; the latter condition shows endothelial dysfunction, per se. The 2 endothelial factors have different origin and may provide different information about endothelial dysfunction in CHF and after HTX caused by idiopathic dilated cardiomyopathy. METHODS: We investigated plasma endothelin and vWF, the relation between these 2 factors, and determinants of endothelin and vWF plasma levels in 32 healthy controls, 25 patients with CHF, and 22 patients who had HTX; both conditions were caused by idiopathic dilated cardiomyopathy. RESULTS: Plasma endothelin was elevated in CHF (6.8 +/- 3.4 pg/mL) and after HTX (6.1 +/- 2.1) compared with healthy controls (4.0 +/- 1.0, P <.0001 for both). VWF was also elevated in CHF (1.6 +/- 0.6 U/mL) and after HTX (2.6 +/- 1.0) compared with healthy controls (1.0 +/- 0.5, P <.0001 for both). VWF was increased after HTX compared with CHF (P <.001), in contrast to similar endothelin levels in CHF and after HTX. Plasma endothelin and vWF correlated in both CHF (r = 0.65, P <.001) and HTX (r = 0.66, P <. 001) but not in controls. In CHF, New York Heart Association functional class was an independent determinant of vWF (P <.0001) and furosemide dose of endothelin (P <.0001). In cardiac transplant recipients, plasma albumin was an independent determinant of vWF (P <.01), and plasma sodium and furosemide dose were independent determinants of endothelin (P <.01). CONCLUSIONS: Plasma endothelin and vWF were directly correlated in both CHF and after HTX caused by idiopathic dilated cardiomyopathy. However, the production of the 2 factors appeared to be stimulated by different mechanisms and provided different information about endothelial function, as indicated by the different determinants and different response to heart transplantation.

Adult↗

Estradiol accelerates functional endothelial recovery after arterial injury.

BACKGROUND: The mechanisms of the established atheroprotective effects of estrogen have not been entirely clarified. Recent data suggest that agents that hasten the recovery of the endothelium after denuding injury will deter the development of neointimal lesions. Because estrogen has been shown to exert angiogenic effects in vitro and in vivo, we performed a series of experiments to evaluate whether estrogen was capable of accelerating reendothelialization. METHODS AND RESULTS: Ovariectomized Sprague-Dawley rats received estrogen replacement therapy in the form of subcutaneously implanted pellets designed to release 1.5 or 5.0 mg 17 beta-estradiol over 30 days. Deendothelializing balloon injury was performed 1 week after pellet implantation, and animals were euthanatized after 1 week for evaluation of reendothelialization (Evans blue staining) or 2 weeks for evaluation of reendothelialization and neointimal formation. At both time points, the use of estradiol caused a dose-dependent increase in reendothelialization, which was measured as absolute area and percentage of area that is reendothelialized. Estradiol accelerated functional endothelial recovery, manifested as an increase in nitric oxide production. Neointimal thickening was also shown to be inhibited in a dose-dependent fashion. CONCLUSIONS: Estrogen accelerates functional endothelial recovery after barotraumatic deendothelializing injury. These findings, along with the recent demonstration of estrogen receptor expression by endothelial cells, suggest that the antiatherogenic action of estrogen may be mediated in part through direct effects on endothelial cells.

Angioplasty, Balloon↗

In vivo/in vitro comparison of rat abdominal aorta wall viscosity. Influence of endothelial function.

Arterial wall viscosity (AWV) is a potential source of energy dissipation in circulation. That arteries, which are known to be markedly viscous in vitro, have lower viscosity in vivo has been suggested but not demonstrated under similar pressure conditions. Endothelium, which may modulate AWV through smooth muscle tone, could contribute to the low level of viscosity in vivo. Our objectives were first to compare AWV of the rat abdominal aorta, in vivo and in vitro, with similar pulse-pressure waves, and second, to determine whether endothelial function influences AWV in vivo and in vitro. The diameter of the abdominal aorta and distending pressure were measured in vivo and in vitro with a high-resolution echotracking system and a micromanometer, respectively. AWV was calculated as the area of the pressure-volume curve hysteresis. After in vivo examination, the arterial segments were isolated in vitro and submitted to resynthesized pressure waves identical to those recorded in vivo. Deendothelialization was performed in vivo by balloon rubbing; then arteries were examined either in vivo or in vitro. AWV was markedly lower in vivo than in vitro (6.6 +/- 0.7 versus 22.7 +/- 3.7 J.m-1.10(-5), respectively; P < .001). After deendothelialization, a sustained 40% increased AWV was observed during a 15-minute follow-up (P < .01). In vitro, deendothelialized arteries have a 64% higher AWV than segments with endothelium (P < .01). Our results indicate that the physiological effective viscosity, measured in vivo in intact animals, is threefold lower than the intrinsic viscosity of the arterial wall, measured in vitro. Endothelium removal determines a sustained increase in AWV, either in vivo or in vitro. These results suggest that active mechanisms compensate for intrinsic viscosity under physiological conditions. One of these energy-saving mechanisms might be dependent on normal endothelial function.

Animals↗