Diffusion-weighted MRI in metastatic gastrointestinal tumors (GIST): A pilot study on the assessment of treatment response in comparison with 18F-FDG PET/CT

Purpose: To evaluate the clinical potential of diffusion-weighted MR imaging with apparent diffusion coefficient (ADC) mapping for the assessment of gastrointestinal stromal tumor (GIST) response to targeted therapy in comparison with 18F-FDG PET/CT. Methods and materials: Five patients (3W/2M, aged 56 ± 13 y) with metastatic GIST underwent both a 18F-FDG PET/CT (Discovery LS, GE Healthcare) and a MRI (VIBE T1 Gd, DWI [b = 50,300,600] and ADC mapping) before and after change in therapy. Exams were first analyzed blindly, then PET/CT images were coregistered to T1 Gd MR images for lesion detection. SUVmax and ADC were measured for the six largest lesions on MRI. The relationship between SUVmax and ADC was analyzed using Spearman's correlation. Results: Altogether, 24 lesions (15 hepatic and 9 non-hepatic) were analyzed on both modalities. Three PET/CT lesions (12.5%) were initially not considered on ADC and 4 lesions on the second PET/CT were excluded because of hepatic vascular activity spillover. SUVmax decreased from 7.2 ± 7.7 g/mL to 5.9 ± 5.9 g/mL (P = 0.53) and ADC increased from 1.2x10-3 mm2/s ± 0.4 to 1.4x10-3 mm2/s ± 0.4 (P = 0.07). There was a significant association between SUVmax decrease and ADC increase (rho= -0.64, P = 0.004). Conclusion: Changes in ADC from diffusion-weighted MRI reflect response of 18F-FDG-avid GIST to therapy. The exact diagnostic value of DWI needs to be investigated further, as well as the effect of lesion size and time under therapy before imaging. Furthermore, the proven association between SUVmax and ADC may be useful for the assessment of treatment response in 18F-FDG non-avid GIST.

Diffusion-weighted MRI in metastatic gastrointestinal tumours (GIST): a pilot study on the assessment of treatment response in comparison with 18 F-FDG PET/CT

Purpose: To evaluate the clinical potential of diffusion-weighted MR imaging with apparent diffusion coefficient (ADC) mapping for the assessment of gastrointestinal stromal tumour (GIST) response to targeted therapy in comparison with 18F-FDG PET/CT Methods and Materials: Five patients (3 W/2M, aged 56±13 y) with metastatic GIST underwent both a 18F-FDG PET/CT (Discovery LS, GE Healthcare) and a MRI (VIBE T1 Gd, DWI [b = 50,300,600] and ADC mapping) before and after change in therapy. Exams were first analysed blindly and then PET/CT images were coregistered to T1 Gd MR images for lesion detection. SUVmax and ADC were measured for the six largest lesions on MRI. The relationship between SUVmax and ADC was analysed using Spearman's correlation. Results: Altogether, 24 lesions (15 hepatic and 9 non-hepatic) were analysed on both modalities. Three PET/CT lesions (12.5%) were initially not considered on ADC and 4 lesions on the second PET/CT were excluded because of hepatic vascular activity spillover. SUVmax decreased from 7.2±7.7 g/mL to 5.9±5.9 g/mL (P = 0.53) and ADC increased from 1.2x10-3 mm2/s ± 0.4 to 1.4x10-3 mm2/s ± 0.4 (P = 0.07). There was a significant association between SUVmax decrease and ADC increase (rho= -0.64, P = 0.004). Conclusion: Changes in ADC from diffusion-weighted MRI reflect response of 18F-FDG-avid GIST to therapy. The exact diagnostic value of DWI needs to be investigated further, as well as the effect of lesion size and time under therapy before imaging. Furthermore, the proven association between SUVmax and ADC may be useful for the assessment of treatment response in 18F-FDG non-avid GIST.

Cilengitide: an integrin-targeting arginine-glycine-aspartic acid peptide with promising activity for glioblastoma multiforme.

BACKGROUND: Glioblastoma multiforme (GBM), a highly invasive and vascular cancer, responds poorly to conventional cytotoxic therapy. Integrins, widely expressed in GBM and tumor vasculature, mediate cell survival, migration and angiogenesis. Cilengitide is a potent alphavbeta3 and alphavbeta5 integrin inhibitor. OBJECTIVE: To summarize the preclinical and clinical experience with cilengitide for GBM. METHODS: Preclinical studies and clinical trials evaluating cilengitide for GBM were reviewed. RESULTS/CONCLUSIONS: Cilengitide is active and synergizes with external beam radiotherapy in preclinical GBM models. In clinical trials for recurrent GBM, single-agent cilengitide has antitumor benefits and minimal toxicity. Among newly diagnosed GBM patients, single-arm studies incorporating cilengitide into standard external beam radiotherapy/temozolomide have shown encouraging activity with no increased toxicity and have led to a planned randomized Phase III trial.

The forgotten face of regular physical exercise: a 'natural' anti-atherogenic activity.

Humans are not programmed to be inactive. The combination of both accelerated sedentary lifestyle and constant food availability disturbs ancient metabolic processes leading to excessive storage of energy in tissue, dyslipidaemia and insulin resistance. As a consequence, the prevalence of Type 2 diabetes, obesity and the metabolic syndrome has increased significantly over the last 30 years. A low level of physical activity and decreased daily energy expenditure contribute to the increased risk of cardiovascular morbidity and mortality following atherosclerotic vascular damage. Physical inactivity leads to the accumulation of visceral fat and consequently the activation of the oxidative stress/inflammation cascade, which promotes the development of atherosclerosis. Considering physical activity as a 'natural' programmed state, it is assumed that it possesses atheroprotective properties. Exercise prevents plaque development and induces the regression of coronary stenosis. Furthermore, experimental studies have revealed that exercise prevents the conversion of plaques into a vulnerable phenotype, thus preventing the appearance of fatal lesions. Exercise promotes atheroprotection possibly by reducing or preventing oxidative stress and inflammation through at least two distinct pathways. Exercise, through laminar shear stress activation, down-regulates endothelial AT1R (angiotensin II type 1 receptor) expression, leading to decreases in NADPH oxidase activity and superoxide anion production, which in turn decreases ROS (reactive oxygen species) generation, and preserves endothelial NO bioavailability and its protective anti-atherogenic effects. Contracting skeletal muscle now emerges as a new organ that releases anti-inflammatory cytokines, such as IL-6 (interleukin-6). IL-6 inhibits TNF-α (tumour necrosis factor-α) production in adipose tissue and macrophages. The down-regulation of TNF-α induced by skeletal-muscle-derived IL-6 may also participate in mediating the atheroprotective effect of physical activity.

Placental growth factor contributes to micro-vascular abnormalization and blood-retinal barrier breakdown in diabetic retinopathy.

OBJECTIVE: There are controversies regarding the pro-angiogenic activity of placental growth factor (PGF) in diabetic retinopathy (DR). For a better understanding of its role on the retina, we have evaluated the effect of a sustained PGF over-expression in rat ocular media, using ciliary muscle electrotransfer (ET) of a plasmid encoding rat PGF-1 (pVAX2-rPGF-1). MATERIALS AND METHODS: pVAX2-rPGF-1 ET in the ciliary muscle (200 V/cm) was achieved in non diabetic and diabetic rat eyes. Control eyes received saline or naked plasmid ET. Clinical follow up was carried out over three months using slit lamp examination and fluorescein angiography. After the control of rPGF-1 expression, PGF-induced effects on retinal vasculature and on the blood-external barrier were evaluated respectively by lectin and occludin staining on flat-mounts. Ocular structures were visualized through histological analysis. RESULTS: After fifteen days of rPGF-1 over-expression in normal eyes, tortuous and dilated capillaries were observed. At one month, microaneurysms and moderate vascular sprouts were detected in mid retinal periphery in vivo and on retinal flat-mounts. At later stages, retinal pigmented epithelial cells demonstrated morphological abnormalities and junction ruptures. In diabetic retinas, PGF expression rose between 2 and 5 months, and, one month after ET, rPGF-1 over-expression induced glial activation and proliferation. CONCLUSION: This is the first demonstration that sustained intraocular PGF production induces vascular and retinal changes similar to those observed in the early stages of diabetic retinopathy. PGF and its receptor Flt-1 may therefore be looked upon as a potential regulatory target at this stage of the disease.

Decreased acute vascular remodeling, anaphylaxis and delayed type hypersensitivity in PPARβ/δ-deficient mice

Endothelial cells form a semi-permeable barrier that participates in the exchange of plasma fluids, proteins and cells, and helps to maintain the physiological functions of organs as well as circulatory homeostasis. Vascular permeability and vasodilatation are increased during acute and chronic inflammation, cancer and wound healing. This is mediated by exposure to certain vascular permeability increasing factors, such as vascular endothelial growth factor (VEGF). The peroxisome proliferator-activated receptors (PPAR) belong to the nuclear hormone receptor (NHRs) family of ligand-activated transcription factors. Three isotypes, PPARa, PPARp/5 and PPARy have been identified. They are all expressed in endothelial cells (ECs). Recent data have demonstrated their involvement in important mechanisms for vasculogenesis and angiogenesis, such as cell proliferation/differentiation, directional sensing/migration, and survival. PPARs were reported to modulate the expression of pro-angiogenic soluble factors, such as VEGF-A and may also participate in the regulation of expression of VEGF receptors. The aim of the present work was to elucidate the role of PPARp/δ in endothelial cell functions important for angiogenesis as well as in vascular permeability and vasodilatation. Using organ culture models of mouse aorta expiants, cultures of human umbilical vein endothelial cells (HUVECs) and genetically modified mouse models, we studied the consequences of loss and gain of PPARp/5 activity on endothelial cell functions. In the first part of this study, we show that the activation of PPARp/δ promotes EC outgrowth in murine aorta expiants. In vivo we observed that dermal vessel acute permeability in response to VEGF-A stimulation is strongly impaired in PPARfi/δ -I- animals. Additionally, observation of the dermal vessel morphology showed a clear enlargement of the wild-type dermal vessels upon VEGF-A injection, whereas vessels of PPARp/5 -/- animals showed almost no enlargement. The impaired response to VEGF stimulation in the knock-out animals was not due to structural or morphological abnormalities. Based on this data, we suggest that PPARp/5 may act on intracellular signaling cascades in ECs, downstream of the VEGF-A receptor. In the second part of this study, we address the relevance of PPARβ/δ vascular functions in pathophysiological inflammatory conditions, such as delayed- type hypersensitivity (DTH) reaction and anaphylaxis in mice. The DTH reaction is a cell-mediated immune reaction to protein, bacterial and viral antigens, whereas anaphylaxis is the most severe form of allergic reaction. In these in vivo models, we demonstrated that the absence of PPARβ/δ in ECs prevents the formation of severe edema in the DTH reaction, and that Ρ PARβ/δ accelerates recovery following systemic anaphylaxis, at least partially through the control of vascular permeability. Our data not only describe a novel function of PPARβ/δ in vessel permeability and vasodilatation, but also open new routes of research for the development of vessel permeability/vasodilatation regulating agents. - Les cellules endothéliales qui bordent la face interne des vaisseaux sanguins forment l'endothélium, une barrière semi-perméable qui régule les échanges de fluides, de protéines et de cellules immunes entre la circulation et les organes. L'endothélium participe également au maintien de la fonction des organes et de l'homéostasie circulatoire. La perméabilité vasculaire augmente dans des situations inflammatoires aigties ou chroniques, dans les tumeurs, et pendant la réparation de blessures. Cette augmentation de perméabilité est due à la production de facteurs sécrétés, tels que le Vascular Endothelial Growth Factor (VEGF-A), la thrombine ou I'histamine. Lès récepteurs nucléaires Peroxisome Proliferator-Activated Receptors (PPAR) sont des facteurs de transcription mis en activité par des ligands. Trois isotypes de PPARs, PPARa, ΡΡΑΡβ/δ and PPARy ont été caractérisés. Ils sont exprimés dans les cellules endothéliales, et des travaux récents ont montré qu'ils régulent des comportements cellulaires importants pour la vasculogenèse et l'angiogenèse, tels que la prolifération, la différenciation, la migration, et la survie des cellules. Ils régulent également la production de VEGF-A par divers types cellulaires. Le but de ce travail était d'élucider le rôle de PPARβ/δ dans la régulation de la perméabilité vasculaire, plus particulièrement dans les cellules endothéliales. Grâce à des cultures d'expiants d'aortes de souris, à la culture d'une lignée endothéliale humaine (HUVECs) et de souris génétiquement modifiées, nous avons étudié le rôle de PPARβ/δ dans les cellules endothéliales, dans des situations gain et perte de fonction du récepteur. Dans la première partie de ce travail, nous avons montré les propriétés pro-angiogéniques de PPARβ/δ dans des explants d'aortes. In vivo, nous avons observé l'absence d'hyperperméabilité aiguë induite par le VEGF-A, la thrombine et I'histamine chez les souris PPARβ/δ -/-. De plus, l'analyse morphologique des vaisseaux dans le derme des souris après stimulation par VEGF- A a confirmé l'absence de réponse à la stimulation. Ces analyses morphologiques nous ont également permis de montrer que l'absence de réponse aiguë n'était pas due à un défaut de structure des vaisseaux dermiques chez les souris PPARp/δ -/-. Sur la base de ces résultats, nous proposons que PPARp/δ régule des voies de signalisation intracellulaires dans les cellules endothéliales, voie de signalisation impliquées dans la régulation de la perméabilité vasculaire: Dans la seconde partie du travail, nous avons étudié l'importance de la régulation de la perméabilité vasculaire par PPARβ/δ dans des situations pathophysiologiques impliquant une hyperperméabilité aiguë des vaisseaux : une réaction d'hypersensibilité cutanée retardée d'une part (delayed-type hypersensitivity, DTH), et un choc anaphylactique d'autre part. Dans ces deux modèles induits expérimentalement chez la souris, l'absence de PPARβ/δ prévient en partie la formation de l'oedème inflammatoire local (DTH), et accélère la récupération (anaphylaxie), au moins partiellement en réglant la perméabilité vasculaire. Ces résultats ouvrent un nouveau champs d'étude quant au rôle de PPARβ/δ dans les vaisseaux et à d'éventuelles applications thérapeutiques dans des pathologies inflammatoires.

Upregulation of vasopressin V1A receptor mRNA and protein in vascular smooth muscle cells following cyclosporin A treatment.

1. The major side effects of the immunosuppressive drug cyclosporin A (CsA) are hypertension and nephrotoxicity. It is likely that both are caused by local vasoconstriction. 2. We have shown previously that 20 h treatment of rat vascular smooth muscle cells (VSMC) with therapeutically relevant CsA concentrations increased the cellular response to [Arg8]vasopressin (AVP) by increasing about 2 fold the number of vasopressin receptors. 3. Displacement experiments using a specific antagonist of the vasopressin V1A receptor (V1AR) showed that the vasopressin binding sites present in VSMC were exclusively receptors of the V1A subtype. 4. Receptor internalization studies revealed that CsA (10(-6) M) did not significantly alter AVP receptor trafficking. 5. V1AR mRNA was increased by CsA, as measured by quantitative polymerase chain reaction. Time-course studies indicated that the increase in mRNA preceded cell surface expression of the receptor, as measured by hormone binding. 6. A direct effect of CsA on the V1AR promoter was investigated using VSMC transfected with a V1AR promoter-luciferase reporter construct. Surprisingly, CsA did not increase, but rather slightly reduced V1AR promoter activity. This effect was independent of the cyclophilin-calcineurin pathway. 7. Measurement of V1AR mRNA decay in the presence of the transcription inhibitor actinomycin D revealed that CsA increased the half-life of V1AR mRNA about 2 fold. 8. In conclusion, CsA increased the response of VSMC to AVP by upregulating V1AR expression through stabilization of its mRNA. This could be a key mechanism in enhanced vascular responsiveness induced by CsA, causing both hypertension and, via renal vasoconstriction, reduced glomerular filtration.

Hormonal, global, and regional haemodynamic responses to a vascular antagonist of vasopressin in patients with congestive heart failure with and without hyponatraemia.

The pathophysiological role of an increase in circulating vasopressin in sustaining global and regional vasoconstriction in patients with congestive heart failure has not been established, particularly in patients with hyponatraemia. To assess this further, 20 patients with congestive heart failure refractory to digoxin and diuretics were studied before and 60 minutes after the intravenous injection (5 micrograms/kg) of the vascular antagonist of vasopressin [1(beta-mercapto-beta,beta-cyclopentamethylene-propionic acid), 2-(0-methyl) tyrosine] arginine vasopressin. Ten patients were hyponatraemic (plasma sodium less than 135 mmol/l) and 10 were normonatraemic. In both groups of patients the vascular vasopressin antagonist did not alter systemic or pulmonary artery pressures, right atrial pressure, pulmonary capillary wedge pressure, cardiac index, or vascular resistances. Furthermore, there was no change in skin and hepatic blood flow in either group after the injection of the vascular antagonist. Only one patient in the hyponatraemic group showed considerable haemodynamic improvement. He had severe congestive heart failure and a high concentration of plasma vasopressin (51 pmol/l). Plasma renin activity, vasopressin, or catecholamine concentrations were not significantly changed in response to the administration of the vasopressin antagonist in either the hyponatraemic or the normonatraemic groups. Patients with hyponatraemia, however, had higher baseline plasma catecholamine concentrations, heart rate, pulmonary pressure and resistance, and lower hepatic blood flow than patients without hyponatraemia. Plasma vasopressin and plasma renin activity were slightly, though not significantly, higher in the hyponatraemic group. Thus the role of vasopressin in sustaining regional or global vasoconstriction seems limited in patients with congestive heart failure whether or not concomitant hyponatraemia is present. Vasopressin significantly increases the vascular tone only in rare patients with severe congestive heart failure and considerably increased vasopressin concentrations. Patients with hyponatraemia do, however, have raised baseline catecholamine concentrations, heart rate, pulmonary arterial pressure and resistance, and decreased hepatic blood flow.

Oxidative-nitrosative stress and systemic vascular function in highlanders with and without exaggerated hypoxemia.

BACKGROUND: Acute exposure to high altitude stimulates free radical formation in lowlanders, yet whether this persists during chronic exposure in healthy, well-adapted and maladapted highlanders suffering from chronic mountain sickness (CMS) remains to be established. METHODS: Oxidative-nitrosative stress (as determined by the presence of the biomarkers ascorbate radical [A •- ], via electron paramagnetic resonance spectroscopy, and nitrite [NO 2 2 ], via ozone-based chemiluminescence) was assessed in venous blood of 25 male highlanders in Bolivia living at 3,600 m with CMS (n 5 13, CMS 1 ) and without CMS (n 5 12, CMS 2 ). Twelve age- and activity-matched, healthy, male lowlanders were examined at sea level and during acute hypoxia. We also measured fl ow-mediated dilatation (FMD), arterial stiffness defined by augmentation index normalized for a heart rate of 75 beats/min (AIx-75), and carotid intima-media thickness (IMT). RESULTS: Compared with normoxic lowlanders, oxidative-nitrosative stress was moderately increased in the CMS 2 group ( P , .05), as indicated by elevated A •- (3,191 457 arbitrary units [AU] vs 2,640 445 AU) and lower NO 2 2 (206 55 nM vs 420 128 nM), whereas vascular function remained preserved. This was comparable to that observed during acute hypoxia in lowlanders in whom vascular dysfunction is typically observed. In contrast, this response was markedly exaggerated in CMS 1 group (A •- , 3,765 429 AU; NO 2 2 , 148 50 nM) compared with both the CMS 2 group and lowlanders ( P , .05). This was associated with systemic vascular dysfunction as indicated by lower ( P , .05 vs CMS 2 ) FMD (4.2% 0.7% vs 7.6% 1.7%) and increased AIx-75 (23% 8% vs 12% 7%) and carotid IMT (714 127 m M vs 588 94 m M). CONCLUSIONS: Healthy highlanders display a moderate, sustained elevation in oxidative-nitrosative stress that, unlike the equivalent increase evoked by acute hypoxia in healthy lowlanders, failed to affect vascular function. Its more marked elevation in patients with CMS may contribute to systemic vascular dysfunction.

Exercice physique et artériopathie oblitérante des membres inférieurs [Physical activity and peripheral arterial obstructive disease]

Intermittent claudication (IC) is the most common clinical manifestation of atherosclerotic peripheral arterial disease. Exercise training plays a major role in treating patients with IC. Regular exercise increases functional walking capacity, reduces cardiovascular mortality and improves quality of life. This seems to be achieved by: favorable effect on cardiovascular risk factors, anti-inflammatory effect, increased collateral blood flux, improved rheology profile, endothelial function, fibrinolysis, and muscular metabolism. However, exact mechanisms underlying beneficial effect of exercise remain largely unknown. Exercise modalities will be discussed in this article.

Gene deletion of dopamine beta-hydroxylase and alpha1-adrenoceptors demonstrates involvement of catecholamines in vascular remodeling.

In vitro studies have shown that stimulation of alpha1-adrenoceptors (ARs) directly induces proliferation, hypertrophy, and migration of arterial smooth muscle cells and adventitial fibroblasts. In vivo studies confirmed these findings and showed that catecholamine trophic activity becomes excessive after experimental balloon injury and contributes to neointimal growth, adventitial thickening, and lumen loss. However, past studies have been limited by selectivity of pharmacological agents. The aim of this study, in which mice devoid of norepinephrine and epinephrine synthesis [dopamine beta-hydroxylase (DBH-/-)] or deficient in alpha1-AR subtypes expressed in murine carotid (alpha1B-AR-/- and alpha1D-AR-/-) were used, was to test the hypothesis that catecholamines contribute to wall hypertrophy after injury. At 3 wk after injury of wild-type mice, lumen area and carotid circumference increased significantly, and hypertrophy of media and adventitia was in excess of that needed to restore circumferential wall stress to normal. In DBH-/- and alpha1B-AR-/- mice, increases in lumen area, circumference, and hypertrophy of the media and adventitia were reduced by 50-91%, resulting in restoration of wall tension to nearly normal (DBH-/-) or normal (alpha1B-AR-/-). In contrast, in alpha1D-AR-/- mice, increases in lumen area, circumference, and wall hypertrophy were unaffected and wall thickening remained in excess of that required to return tension to normal. When examined 5 days after injury, proliferation and leukocyte infiltration were inhibited in DBH-/- mice. These studies suggest that the trophic effects of catecholamines are mediated primarily by alpha1B-ARs in mouse carotid and contribute to hypertrophic growth after vascular injury.

Nitric oxide activity through guanylate cyclase and phosphodiesterase modulation is impaired in fetal lambs with congenital diaphragmatic hernia.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is associated with pulmonary hypertension and death. Administration of nitric oxide (NO) alone remains ineffective in CDH cases. We investigated in near full-term lambs with and without CDH the role of guanylate cyclase (GC), the enzyme activated by NO in increasing cyclic 3'-5'-guanylosine monophosphate, and the role of phosphodiesterase (PDE) 5, the enzyme-degrading cyclic 3'-5'-guanylosine monophosphate. METHODS: Congenital diaphragmatic hernia was surgically created in fetal lambs at 85 days of gestation. Pulmonary hemodynamics were assessed by means of pressure and blood flow catheters (135 days). In vitro, we tested drugs on rings of isolated pulmonary vessels. RESULTS: In vivo, sodium nitroprusside, a direct NO donor, and methyl-2(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5 trimethoxyphenyl)-3-isoquinoline carboxylate sulfate (T-1032) and Zaprinast, both PDE 5 blockers, reduced pulmonary vascular resistance in CDH and non-CDH animals. The activation of GC by sodium nitroprusside and the inhibition of PDE 5 by T-1032 were less effective in CDH animals. In vitro, the stimulation of GC by 3(5'hydroxymethyl-2'furyl)-1-benzyl indazole (YC-1) (a benzyl indazole derivative) and the inhibition of PDE 5 by T-1032 were less effective in pulmonary vascular rings from CDH animals. The YC-1-induced vasodilation in rings from CDH animals was higher when associated with the PDE 5 inhibitor T-1032. CONCLUSIONS: Guanylate cyclase and PDE 5 play a role in controlling pulmonary vascular tone in fetal lambs with or without CDH. Both enzymes seem to be impaired in fetal lambs with CDH.

Angiotensin-converting enzyme inhibition improves vascular function in rheumatoid arthritis.

BACKGROUND: The excess in cardiovascular risk in patients with rheumatoid arthritis provides a strong rationale for early therapeutical interventions. In view of the similarities between atherosclerosis and rheumatoid arthritis and the proven benefit of angiotensin-converting enzyme inhibitors in atherosclerotic vascular disease, it was the aim of the present study to delineate the impact of ramipril on endothelial function as well as on markers of inflammation and oxidative stress in patients with rheumatoid arthritis. METHODS AND RESULTS: Eleven patients with rheumatoid arthritis were included in this randomized, double-blind, crossover study to receive ramipril in an uptitration design (2.5 to 10 mg) for 8 weeks followed by placebo, or vice versa, on top of standard antiinflammatory therapy. Endothelial function assessed by flow-mediated dilation of the brachial artery, markers of inflammation and oxidative stress, and disease activity were investigated at baseline and after each treatment period. Endothelial function assessed by flow-mediated dilation increased from 2.85+/-1.49% to 4.00+/-1.81% (P=0.017) after 8 weeks of therapy with ramipril but did not change with placebo (from 2.85+/-1.49% to 2.84+/-2.47%; P=0.88). Although systolic blood pressure and heart rate remained unaltered, diastolic blood pressure decreased slightly from 78+/-7 to 74+/-6 mm Hg (P=0.03). Tumor necrosis factor-alpha showed a significant inverse correlation with flow-mediated dilation (r=-0.408, P=0.02), and CD40 significantly decreased after ramipril therapy (P=0.049). CONCLUSIONS: Angiotensin-converting enzyme inhibition with 10 mg/d ramipril for 8 weeks on top of current antiinflammatory treatment markedly improved endothelial function in patients with rheumatoid arthritis. This finding suggests that angiotensin-converting enzyme inhibition may provide a novel strategy to prevent cardiovascular events in these patients.

Effect of captopril on renal vascular tone in patients with essential hypertension.

1. The effect of acute inhibition of angiotensin-converting enzyme by captopril (50 mg) on renal haemodynamics and function was assessed in nine patients with essential hypertension on unrestricted sodium intake (n = 8) or low sodium diet (n = 1). 2. Captopril induced a rapid and significant decrease in arterial pressure, which was maximal within 60 min. 3. Effective renal plasma flow (ERPF) increased, glomerular filtration rate (GFR) did not change and filtration fraction (FF) decreased after captopril. No change in sodium excretion and a decrease in urinary potassium occurred. 4. In the patient on low sodium diet, captopril induced striking increases in GFR and ERPF (64 and 106% respectively). 5. The logarithm of baseline plasma renin activity was positvely correlated with the change in ERPF and negatively correlated with changes in FF and renal resistance. 6. The results indicate that in patients with essential hypertension angiotensin participates actively in the maintenance of renal vascular tone at the efferent arteriolar level. A possible influence of kinins remains to be defined.

Vascular integrins in tumor angiogenesis: mediators and therapeutic targets.

The notion that tumor angiogenesis may have therapeutic implications in the control of tumor growth was introduced by Dr. Judah Folkman in 1971. The approval of Avastin in 2004 as the first antiangiogenic systemic drug to treat cancer patients came as a validation of this visionary concept and opened new perspectives to the treatment of cancer. In addition, this success boosted the field to the quest for new therapeutic targets and antiangiogenic drugs. Preclinical and clinical evidence indicate that vascular integrins may be valid therapeutic targets. In preclinical studies, pharmacological inhibition of integrin function efficiently suppressed angiogenesis and inhibited tumor progression. alphaVbeta3 and alphaVbeta5 were the first vascular integrins targeted to suppress tumor angiogenesis. Subsequent experiments revealed that at least four additional integrins (i.e., alpha1beta1, alpha2beta1, alpha5beta1, and alpha6beta4) might be potential therapeutic targets. In clinical studies low-molecular-weight integrin inhibitors and anti-integrin function-blocking antibodies demonstrated low toxicity and good tolerability and are now being tested in combination with radiotherapy and chemotherapy for anticancer activity in patients. In this article the authors review the role of integrins in angiogenesis, present recent development in the use of alphaVbeta3 and alpha5beta1 integrin antagonists as potential therapeutics in cancer, and discuss future perspectives.