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Results for “Endothelial function”

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At least 865 records · Page 48Linked to original sources

PubMed2002

Effect of cardiac cycle on ultrasound assessment of endothelial function.

To investigate the effects of non-ECG-triggered imaging during ultrasound studies of endothelial function, brachial artery diameters were measured throughout the cardiac cycle at rest, during reactive hyperemia, and after administration of nitroglycerin. R-wave-triggered imaging using a 7.5-MHz ultrasound transducer with acquisition every 41.7-66.7 ms was performed in 24 subjects. Cardiac cycle-related variation was computed as the maximum per cent change from the end-diastolic diameter. The range of possible errors in flow-mediated dilation (FMD) and nitroglycerin-mediated vasodilation that may result from ignoring cyclic variations in diameter was determined for each condition. True FMD, true nitroglycerin-mediated vasodilation, and the maximum and minimum values that could be erroneously calculated for FMD if timing was ignored all differed dramatically (p < 0.05). The range of apparent FMD values that could be measured was nearly three times the true FMD value. Ignoring temporal position within the cardiac cycle artifactually increased calculated FMD into the normal range, despite truly impaired FMD. Peak arterial dilation occurred before end-systole and greater baseline vessel compliance was associated with greater FMD. Brachial arterial diameters vary significantly throughout the cardiac cycle. The magnitude of this variation is similar to the arterial dilation induced by reactive hyperemia and nitroglycerin, making ECG-triggered imaging mandatory for accurate and reproducible clinical and research measurements of artery diameters and FMD. Measurement of diameters at end-diastole may be preferred to other time-points in the cardiac cycle.

Aged↗

PubMed1998

Preserved endothelial function in IDDM patients, but not in NIDDM patients, compared with healthy subjects.

OBJECTIVE: To examine endothelial function (EF) noninvasively in IDDM and NIDDM patients with long diabetes duration. RESEARCH DESIGN AND METHODS: We studied EF in 17 IDDM patients without diabetic complications and in 25 NIDDM patients with comparable glycemic control and with diabetic complications and compared both with nondiabetic control subjects matched for age, sex, and lumen diameter. Using high-resolution ultrasound, we measured the endothelial-dependent (FAD%) and independent vasodilation (GTN%); the blood flow at rest, postocclusive, and after application of 400 micrograms glyceroltrinitrate of the branchial artery; and the intima media thickness (IMT) of the common carotid artery. RESULTS: In the IDDM patients, neither FAD% (8.2 +/- 4.6 vs. 7.6 +/- 4.2%), GTN% (16.3 +/- 4.9 vs. 18.4 +/- 6.4%), nor postocclusive blood flow (40.6 +/- 19.1 vs. 39.3 +/- 23.6 cm/s) differed from the control subjects. IMT (0.59 +/- 0.10 vs. 0.55 +/- 0.14 mm) was slightly, but not significantly, elevated. In contrast, the NIDDM patients showed an impaired FAD% (3.8 +/- 3.3 vs. 6.9 +/- 4.4%, P < 0.01), no difference in GTN%, and a decreased postocclusive blood flow (18.5 +/- 13.8 vs. 32.7 +/- 20.0 cm/s, P < 0.01). IMT was significantly increased in NIDDM patients (0.77 +/- 0.14 vs. 0.62 +/- 0.10 mm, P < 0.001). CONCLUSIONS: In contrast to NIDDM patients with cardiovascular complications, IDDM patients with long diabetes duration and good long-term metabolic control do not have impaired EF compared with control subjects.

Adult↗

PubMed2005

Hydrogen peroxide regulation of endothelial function: origins, mechanisms, and consequences.

Increased production of reactive oxygen species (ROS) has been implicated in the pathogenesis of cardiovascular diseases. Enzymatic systems such as the mitochondrial respiratory chain, vascular NAD(P)H oxidases, xanthine oxidase, and uncoupled endothelial nitric oxide synthase (eNOS) produce superoxide anion (O2*-) in vascular cells. While some O2(*-) rapidly degrades by reacting with nitric oxide (NO*), the O2*- signal preserved by dismutation into hydrogen peroxide (H2O2) exerts prolonged signaling effects. This review focuses on patterns and mechanisms whereby H2O2 modulates different aspects of endothelial cell function including endothelial cell growth and proliferation, endothelial apoptosis, endothelium-dependent vasorelaxation, endothelial cytoskeletal reorganization and barrier dysfunction, endothelial inflammatory responses, and endothelium-regulated vascular remodeling. These modulations of endothelial cell function may at least partially underlie H2O2 contribution to the development of vascular disease.

Animals↗

PubMed1998

Effect of dorzolamide on corneal endothelial function in normal human eyes.

PURPOSE: To assess the effects of dorzolamide hydrochloride, a topical carbonic anhydrase inhibitor, on corneal endothelial function. METHODS: The authors measured the rate of corneal deswelling and the endothelial permeability to fluorescein after 2 hours of hypoxic contact lens wear in 19 normal human subjects. The study was double-masked; one eye of each subject was randomly assigned to receive 2% dorzolamide drops, and the other eye received placebo drops every 8 hours for 24 hours before the study day and twice during the study day. RESULTS: Dorzolamide-treated eyes were not significantly different from placebo-treated eyes in corneal deswelling rate, expressed as the percent recovery per hour (55.7% +/- 13.6% versus 59.6% +/- 14.5%; P > or = 0.10), open eye steady state thickness, swelling induced by hypoxia, and corneal autofluorescence. Endothelial permeability to fluorescein was increased in the dorzolamide eyes (4.40 +/- 0.84 x 10(-4) cm/minute versus 4.10 +/- 0.80 x 10(-4) cm/minute; P = 0.01). As expected, the intraocular pressure and aqueous humor flow rate were decreased in the dorzolamide eyes. CONCLUSIONS: Dorzolamide hydrochloride, when topically administered to normal human eyes for 24 hours, had no significant effect on the corneal deswelling rate after hypoxic stress. The corneal endothelial permeability to fluorescein, however, was increased by the drug, although this did not result in increased corneal thickness.

Adult↗

PubMed1976

The endothelial function of donor corneas: effects of delayed enucleation and refrigeration.

The endothelial viability of rabbit corneas subjected to various forms of cadaveric and moist chamber storage was evaluated by means of the specular microscope and the rate of stromal deturgescence during a temperature reversal response. Delays in the postmortem enucleation and refrigeration of potential donor corneas was shown to be detrimental to the functioning of the endothelium. To best preserve the endothelial function of donor corneas, the eyes should be removed as soon after death as possible and refrigerated at 4 degrees C. Refrigerated cadaveric storage was found not to be a substitute for early enucleation and refrigeration of the corneas. The limitations in the use of the rate of stromal deturgescence during a temperature reversal response as a quantitative indicator of endothelial function are discussed.

Animals↗

PubMed1994

Endothelial function and serum lipids in the course of developing microalbuminuria in insulin-dependent diabetes mellitus.

Changed endothelial function and dyslipidemia are features of insulin-dependent diabetes mellitus complicated with clinical nephropathy. The time relationship between the appearance of these abnormalities is however not well known. We have therefore studied the coincidence of microalbuminuria, endothelial dysfunction and dyslipidemia during a 10 year prospective study of 209 insulin-dependent diabetic patients with normal urinary albumin excretion. Twenty-three patients developed progressing microalbuminuria defined as a median urinary albumin excretion > 30 mg/24-h in two consecutive years and a progression rate in albuminuria higher than 5% per year. Thirty patients who remained normoalbuminuric throughout the observation period were randomly selected to obtain a control group with comparable degree of glycaemic control. The mean level of von Willebrand factor before onset of microalbuminuria tended to be higher in patients developing microalbuminuria than in the control group (NS), but there was no increase in von Willebrand factor in the patients who developed microalbuminuria. Total cholesterol did not change, but a significant decrease in high density lipoprotein cholesterol was observed in patients who developed microalbuminuria. In conclusion, the study demonstrated coincidence of microalbuminuria and decreasing high density lipoprotein cholesterol, but no coincidence between onset of microalbuminuria and endothelial dysfunction assessed by von Willebrand factor.

Adolescent↗

PubMed2001

Which tools are in your cardiac workshop? Carotid ultrasound, endothelial function, and magnetic resonance imaging.

There are several techniques for assessing arterial health, including carotid ultrasound, endothelial function, and magnetic resonance imaging. Each has pros and cons, but which technique is best? Quantitative intima medial thickness (QIMT) is safe, validated, portable, has a reference database, is inexpensive, and can be used in multicenter studies. Magnetic resonance imaging may be useful clinically, but it is still considered experimental and remains a costly procedure. Flow-mediated dilation (FMD) is a good surrogate measure, reflecting initial risk, indicating very early disease, and demonstrating rapid response to change. All the imaging methods require standardization of tools, operator training, specification of populations studied, and other considerations to be of use in the clinical setting.

Arteriosclerosis↗

PubMedDate not supplied

[Hyperemic reactivity scintigraphy in endothelial function].

OBJECTIVE: The aim of this study was to compare a recently described method to evaluate endothelial function; the hyperemic reactivity scintigraphy (HRS) with the ultrasonographic flow-mediated dilatation (FMD) in brachial artery and its relationship with myocardial SPECT. METHODS: 42 consecutive patients that underwent myocardial scintigraphy were included. Thirty-six patients had simultaneous measurement of FMD. Both studies were obtained after 5 minutes occlusion of the upper arm with a blood pressure cuff inflated at 250 mmHg. HRS was performed dynamically at rate 1 frame/sec during 3 minutes after intravenous injection of 740 MBq of Tc-99 sestamibi. Time-activity curves allowed obtaining the following indexes: medium hyperemic activity/medium contrallateral activity (MHA/MCA) and maximum hyperemic activity/maximum contrallateral activity (MxHA/CxHA). RESULTS: In 13 patients SPECT was normal. Twenty-nine patients had perfusion defects in scintigraphy. There was relationship between the FMD and the MHA/MCA (r = 0.23; p = 0.018) and the FMD and the MxHA/CxHA (r = 0.18; p = 0.05). Patients with alterations in the SPECT had an index MxHA/CxHA lower than patients with normal SPECT (1.8 +/- 0.2 vs 1.5 +/- 0.4; p = 0.04). We did not find relationship between FMD and alterations in SPECT. CONCLUSIONS: There is relationship between FMD and HRS. HRS is lower in patients with perfusion defects in the SPECT. HRS could provide additional value to myocardial scintigraphy.

Aged↗

PubMed2006

Use of a flow-mediated vasodilation technique to assess endothelial function in dogs.

OBJECTIVE: To develop and assess the reproducibility of a protocol to noninvasively test endothelial function in dogs on the basis of the flow-mediated vasodilation (FMD) procedure used in humans. ANIMALS: 5 healthy spayed female dogs. PROCEDURES: Luminal arterial diameter and blood flow velocity in the brachial and femoral arteries were measured with ultrasonography. The within-dog reproducibility of these ultrasonographic measurements was tested. An occlusion period of 1, 3, or 5 minutes with an inflatable cuff was used to create the FMD response. Measurements made at 15, 30, and 60 seconds following release of the occlusion were compared with measurements made immediately prior to each occlusion to assess the FMD response. RESULTS: Within-dog reproducibility of measurements revealed moderate to high correlations. Change from baseline in luminal arterial diameter was most substantial when measured at 30 seconds following release of occlusion, whereas blood flow velocity changes were maximal when measured at 15 seconds following release. The brachial imaging site provided a larger number of significant FMD responses than the femoral site. The 3-minute occlusion period provided equal or better responses than the 5-minute occlusion period. CONCLUSIONS AND CLINICAL RELEVANCE: Ultrasonographic measurement of the FMD responses was a feasible and reproducible technique and significant changes from baseline were detected. The FMD responses in dogs were most substantial when performed at the brachial artery with blood flow velocity and luminal arterial diameter changes from baseline measured at 15 and 30 seconds, respectively, following release of a 3-minute occlusion period.

Animals↗

PubMed1994

Effects of calcium channel blockers on rabbit corneal endothelial function.

The effects of calcium channel antagonists and agents that alter intracellular Ca2+ mobilization on corneal endothelial function have been examined. All experiments, except where specifically designated, were performed in the continuous presence of extracellular Ca2+. Verapamil (at 50 microM) increased the swelling rate of corneas bathed in normal Ringer solution whereas nifedipine and diltiazem (both up to 100 microM) were without effect. The nifedipine analog nisoldipine caused corneal swelling at 10 microM and 50 microM but nimodipine was without effect. When briefly exposed to a Ca(2+)-free solution corneal swelling was enhanced after subsequent exposure to 50 microM verapamil in normal Ringer but not after 50 microM diltiazem in normal Ringer, indicating that Ca2+ entry from the bathing solution into the cell was important and was apparently impeded by verapamil. Cadmium (0.6 and 1 mM) but not nickel (up to 250 microM) caused swelling of corneas bathed in normal Ringer. A Ca2+ channel agonist, BAY-K-8644, alone did not influence corneal thickness but when presented to the endothelium with 50 microM verapamil the swelling rate was much reduced compared to verapamil alone. The agonist, therefore, presumably maintained some Ca2+ channels open in face of the Ca2+ channel blocker. An agent that inhibited the release of intracellular Ca2+ stores (TMB-8) caused an initial corneal swelling over the first 1.5 hr of perfusion but thereafter had no effect on corneal thickness. In the presence of continued extracellular Ca2+ one explanation for the results is that modulation of intracellular Ca2+ by agents that alter plasma membrane transfer of Ca2+ influences apical junction permeability.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2002

The presence of African American race predicts improvement in coronary endothelial function after supplementary L-arginine.

OBJECTIVES: The purpose of our study was to determine if the presence of African American ethnicity modulates improvement in coronary vascular endothelial function after supplementary L-arginine. BACKGROUND: Endothelial dysfunction is an early stage in the development of coronary atherosclerosis and has been implicated in the pathogenesis of hypertension and cardiomyopathy. Amelioration of endothelial dysfunction has been demonstrated in patients with established coronary atherosclerosis or with risk factors in response to infusion of L-arginine, the precursor of nitric oxide. Racial and gender patterns in L-arginine responsiveness have not, heretofore, been studied. METHODS: Invasive testing of coronary artery and microvascular reactivity in response to graded intracoronary infusions of acetylcholine (ACh) +/- L-arginine was carried out in 33 matched pairs of African American and white subjects with no angiographic coronary artery disease. Pairs were matched for age, gender, indexed left ventricular mass, body mass index and low-density lipoprotein cholesterol. RESULTS: In addition to the matching parameters, there were no significant differences in peak coronary blood flow (CBF) response to intracoronary adenosine or in the peak CBF response to ACh before L-arginine infusion. However, absolute percentile improvement in CBF response to ACh infusion after L-arginine, as compared with before, was significantly greater among African Americans as a group (45 +/- 10% vs. 4 +/- 6%, p = 0.0016) and after partitioning by gender. The mechanism of this increase was mediated through further reduction in coronary microvascular resistance. L-arginine infusion also resulted in greater epicardial dilator response after ACh among African Americans. CONCLUSIONS: We conclude that intracoronary infusion of L-arginine provides significantly greater augmentation of endothelium-dependent vascular relaxation in those of African American ethnicity when compared with matched white subjects drawn from a cohort electively referred for coronary angiography. Our findings suggest that there are target populations in which supplementary L-arginine may be of therapeutic benefit in the amelioration of microvascular endothelial dysfunction. In view of the excess prevalence of cardiomyopathy among African Americans, pharmacologic correction of microcirculatory endothelial dysfunction in this group is an important area of further investigation and may ultimately prove to be clinically indicated.

Acetylcholine↗

PubMed1999

Endothelial function and carotid artery wall thickening in patients with early essential hypertension.

To investigate the relationship between endothelial function and carotid artery wall thickening in patients with early mild essential hypertension, the percent dilatation of humerus diameter and intimal-medial thickening (IMT) of common carotid artery was measured by using high-resolution ultrasound in 20 patients with early mild essential hypertension and 18 patients with normotension. The patients with hypertension had not been treated and their history of increased blood pressure was less than 12 months. In essential hypertension group, the percent dilatation of humerus diameter decreased significantly (2.65 +/- 0.98% vs 6.38 +/- 1.61%); IMT of carotid artery increased (0.88 +/- 0.16 mm vs 0.58 +/- 0.08). There was significant negative correlation between IMT and the percent dilatation of humerus diameter (gamma = -0.82, P < 0.05), and no correlation between IMT and 24 h mean systolic, diastolic pressure (gamma = 0.12 and gamma = 0.07, respectively; P > 0.05). Our results suggested that there was endothelial dysfunction in early mild essential hypertension. Endothelial dysfunction may not only contribute to the pathogenesis of hypertension but also serve as the most important inducing factor leading transformation from hypertension to atherosclerosis.

Atherosclerosis↗

PubMed2000

Sialyl LewisX oligosaccharide preserves myocardial and endothelial function during cardioplegic ischemia.

BACKGROUND: Neutrophil adhesion to endothelium contributes to myocardial reperfusion injury after cardiac operation. Initial neutrophil-endothelial interactions involve selectins, which bind Sialyl-LewisX on neutrophils. Blockade of selectin-mediated neutrophil-endothelial interactions with CY-1503, a synthetic analogue of Sialyl-LewisX, might reduce reperfusion injury after myocardial ischemia. METHODS: The efficacy of CY-1503 to attenuate global myocardial reperfusion injury was assessed in isolated blood-perfused neonatal lamb hearts that had 2 hours of cold cardioplegic ischemia. CY-1503 (40 mg/L) or saline vehicle was added to blood perfusate before ischemia. Contractile function (developed pressure, dP/dt) and coronary vascular endothelial function (acetylcholine response) were assessed at base line and during reperfusion. Myocardial neutrophil accumulation was assessed by myeloperoxidase quantification. RESULTS: Compared to controls, treatment with CY-1503 improved recovery of all indices of contractile function, preserved coronary vascular endothelial function, and reduced myocardial neutrophil accumulation. CONCLUSIONS: In isolated neonatal lamb hearts that underwent hypothermic cardioplegic ischemia, CY-1503 administration reduced myocardial neutrophil accumulation and preserved endothelial and contractile function. Selectin blockade of leukocyte-endothelial interactions might attenuate reperfusion injury and enhance myocardial protection during cardiac surgical procedures.

Animals↗

PubMed2006

Impact of coronary endothelial function on the progression of cardiac transplant-associated arteriosclerosis: effect of anti-oxidant vitamins C and E.

BACKGROUND: Excessive vascular oxidant stress has been implicated in cardiac transplant-associated arteriosclerosis (TxAA). In a recent placebo-controlled study of 40 cardiac transplant recipients, vitamin C 500 mg twice a day and vitamin E 400 IU twice a day for 1 year retarded the progression of TxAA, as assessed by intravascular ultrasound (IVUS). Endothelial dysfunction is a key feature of TxAA and reflects oxidant stress. We hypothesized that coronary endothelial dysfunction portends greater TxAA progression and a larger therapeutic response to anti-oxidant vitamins. METHODS: In this pre-specified analysis, the 40 cardiac transplant recipients were categorized according to normal or abnormal coronary endothelial vasomotor function at baseline, as assessed by acetylcholine (10(-8) to 10(-6) mol/liter). The effect of anti-oxidant vitamins within these two groups of patients was assessed by the change in intimal index over 1 year using IVUS. RESULTS: With placebo (n = 21), the increase in intimal index was greater in the presence vs absence of endothelial dysfunction (11 +/- 3% vs 5 +/- 1%, p < 0.05). Among patients with endothelial dysfunction (n = 21), the intimal index increased 11 +/- 3% with placebo, but decreased -1 +/- 2% with vitamins (p = 0.002). Among patients with normal endothelial function (n = 14), the intimal index increased 5 +/- 1% with placebo and 1 +/- 1% with vitamins (p < 0.05). CONCLUSIONS: Endothelial dysfunction indicates rapid TxAA progression, even in the statin era. Although anti-oxidant vitamins reduce disease progression in patients with normal or abnormal endothelial function, the magnitude of benefit is larger in patients with endothelial dysfunction.

Antioxidants↗

PubMed2000

Does a glass of red wine improve endothelial function?

AIMS: To examine the acute effect of red wine and de-alcoholized red wine on endothelial function. METHODS AND RESULTS: High frequency ultrasound was used to measure blood flow and percentage brachial artery dilatation after reactive hyperaemia induced by forearm cuff occlusion in 12 healthy subjects, less than 40 years of age, without known cardiovascular risk factors. The subjects drank 250 ml of red wine with or without alcohol over 10 min according to a randomized procedure. Brachial artery dilatation was measured again 30 and 60 min after the subjects had finished drinking. The subjects were studied a second time within a week of the first study in a cross-over design. After the red wine with alcohol the resting brachial artery diameter, resting blood flow, heart rate and plasma-ethanol increased significantly. After the de-alcoholized red wine these parameters were unchanged. Flow-mediated dilatation of the brachial artery was significantly higher (P<0.05) after drinking de-alcoholized red wine (5.6+/-3.2%) than after drinking red wine with alcohol (3.6+/-2.2%) and before drinking (3.9+/-2.5%). CONCLUSION: After ingestion of red wine with alcohol the brachial artery dilated and the blood flow increased. These changes were not observed following the de-alcoholized red wine and were thus attributable to ethanol. These haemodynamic changes may have concealed an effect on flow-mediated brachial artery dilatation which did not increase after drinking red wine with alcohol. Flow-mediated dilatation of the brachial artery increased significantly after de-alcoholized red wine and this finding may support the hypothesis that antioxidant qualities of red wine, rather than ethanol in itself, may protect against cardiovascular disease.

Adult↗

PubMed2001

Acute and mid-term combined hormone replacement therapy improves endothelial function in post-menopausal women with angina and angiographically normal coronary arteries.

AIMS AND BACKGROUND: Coronary endothelial dysfunction improves after acute oestradiol treatment in women with angina and normal coronary angiograms. We sought to analyse whether this effect is also seen in the peripheral circulation and whether it is sustained after a mid-term period of treatment. METHODS: We studied 20 women with angina, signs suggestive of myocardial ischaemia and normal coronary angiograms. In five of them, coronary and peripheral endothelial functions were studied at baseline. Brachial artery flow-mediated dilation was reanalysed after 24 h of transdermal oestradiol treatment. In the other 15 women, brachial artery vasoreactivity was studied at baseline and after a 6-week period of treatment with transdermal oestradiol and medroxyprogesterone (HRT) or placebo in a double-blinded crossover fashion. RESULTS: An abnormal coronary artery response to acetylcholine was observed in all women as well as impaired brachial flow-mediated dilation. Brachial flow-mediated dilation significantly increased after 24 h of oestradiol treatment (4.8+/-0.8% vs 0.06+/-0.6%, P<0.001). Peripheral flow-mediated dilation also increased after a 6-week period of HRT compared with baseline (4.1+/-3% vs 0.4+/-1%, P<0.01) and placebo treatment (4.1+/-3% vs 0.6+/-1.7%, P<0.01). CONCLUSION: Impaired endothelium-dependent vasodilation exists both at the coronary and peripheral circulation in post-menopausal women with angina and normal coronary angiograms. Flow-mediated dilation improves in these women after short and mid-term therapy with transdermal oestradiol irrespective of concomitant progesterone use.

Aged↗

PubMedDate not supplied

[Endothelial function of normotensive adolescents with no risk factors for arterial hypertension].

OBJECTIVE: To define standards for normal endothelial function in adolescents by high-resolution ultrasound measurement of endothelium-dependent vascular dilatation. METHODS: This was a cross-sectional, descriptive, observational study and part of the thematic project "Clinical Study of Growth, Behavior, Arterial Hypertension, Obesity and Oral Health" (ECCCHOS) that was developed by the Discipline of Nutrition at the Universidade Federal de São Paulo. Thirty-one adolescents, eight male and twenty-three female, with no risk factors for systemic arterial hypertension were selected from 1,420 secondary school students. The students were daytime pupils at a school in the southeastern district of the city of São Paulo, the capital of São Paulo state, located in the Southeast region of Brazil. All results are presented in the form of means with standard deviations and percentiles. RESULTS: For male students, endothelium-dependant dilation 90 seconds after the cuff was released was 20.9+/-6.7% [mean +/-1 standard deviation] with a 10th percentile of 12.5 and for females these figures were 18.8+/-12.9% with a 10th percentile of 6.6%. Values for the whole group of subjects were 19.3+/-11.7% and 6.7%, respectively. CONCLUSION: Endothelium-dependant vascular dilation of 6.7%, after 90 seconds, which corresponds to the 10th percentile, can be considered the lower limit of normality for this age group. Knowledge of this limit is important for the diagnosis of endothelium dysfunction that appears before cardiovascular disease.

Adolescent↗

PubMed2005

Extracellular matrix regulates endothelial functions through interaction of VEGFR-3 and integrin alpha5beta1.

Endothelium extracellular matrix (ECM) interactions can provide distinct spatial and molecular signals which control cellular proliferation, migration, and differentiation. Here, we investigated the role of fibronectin (FN), a major ECM protein, on the functions of lymphatic endothelial cells (LEC). We observed that FN, the ligand for integrin alpha5beta1, selectively promoted the growth of LEC as compared with vitronectin (VN) in the presence of the ligand for vascular endothelial growth factor receptor 3 [VEGFR-3 (VEGF-C156S)]. Upon investigating the mechanisms whereby ECM components regulate VEGFR-3 signaling, we found that FN transactivated VEGFR-3 and significantly enhanced the phosphorylation of VEGFR-3 induced by VEGF-C156S as compared to VN. An enhanced association of the integrin subunit alpha5 or beta1 with VEGFR-3, after stimulation with VEGF-C156S, was observed by co-immunoprecipitation. While blockade of integrin alpha5beta1 inhibited the VEGF-C156S-induced phosphorylation of VEGFR-3, no similar effect was obtained by blocking integrin alphavbeta3. FN also protected the endothelial cells from serum deprivation-induced apoptosis. Moreover, while the specific PI3 kinase inhibitor, LY294002, abolished this FN-mediated cell survival, the MAPK kinase inhibitor, PD98059, had no significant effect. Furthermore, a dominant-negative mutant of VEGFR-3 (G857R) reduced VEGF-C156S or FN-mediated cell survival, as well as the activities of PI3 kinase/Akt. Our results indicate that integrin alpha5beta1 participates in the activation of both VEGFR-3 and its downstream PI3 kinase/Akt signaling pathway, which is essential for FN-mediated lymphatic endothelial cell survival and proliferation.

Apoptosis↗