Insulin suppresses plasma concentration of vascular endothelial growth factor and matrix metalloproteinase-9

OBJECTIVE: We recently demonstrated a potent anti-inflammatory and thus a potential antiatherogenic effect of insulin in human aortic endothelial cells and mononuclear cells at physiologically relevant concentrations. We have now further investigated the anti-inflammatory suppressive action of insulin on vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9. VEGF and MMP-9 play a central regulatory role in angiogenesis, contribute to the pathogenesis of proliferative retinopathy, and have also been found to accelerate atherosclerosis. RESEARCH DESIGN AND METHODS: Insulin was infused (2 IU/h) in 5% dextrose (100 ml/h) and KCl (8 mmol/h) into 10 fasting, obese, nondiabetic subjects for 4 h. Subjects were also infused with 5% dextrose without insulin and with saline on two separate occasions. Blood samples were obtained at 0, 2, 4, and 6 h. RESULTS: Plasma insulin concentrations increased from a basal level of 12.5 +/- 2.2 to 28.2 +/- 3.3 micro U/ml at 2 h and 24.4 +/- 3.7 micro U/ml at 4 h after insulin infusion. VEGF concentration decreased from 307.2 +/- 163.8 pg/ml (100%) at 0 h to 73.5 +/- 20.9% of the basal level at 2 h and 67.1 +/- 23.2% at 4h. Plasma MMP-9 concentrations decreased from 375 +/- 196.3 ng/ml (100%) at 0 h to 83 +/- 22% of the basal level at 2 h and to 82 +/- 21% of the basal level at 4 h (P < 0.05). Dextrose infusion alone did not change plasma VEGF concentration. However, plasma MMP-9 concentration increased significantly at 4 h following dextrose infusion alone (P < 0.05). Saline infusions without insulin caused no alteration in glucose, insulin, VEGF, or MMP-9. CONCLUSIONS: These observations may have implications for a potential antiretinopathic and antiatherosclerotic effect of insulin in the long term.     

Blood levels of angiogenin and vascular endothelial growth factor are elevated in myelodysplastic syndromes and in acute myeloid leukemia

Angiogenesis is of prognostic importance not only in solid tumors but also in malignant blood diseases. We measured levels of vascular endothelial growth factor (VEGF), angiogenin (ANG), and basic fibroblast growth factor (bFGF) in peripheral blood samples from 65 patients with myelodysplastic syndrome (MDS), from 25 patients with de novo acute myeloid leukemia (AML), and from 50 healthy donors. In matched samples, VEGF levels in serum were substantially higher than VEGF levels in plasma (380.7 +/- 56 pg/ml vs. 45.3 +/- 4.5 pg/ml, mean +/- SEM, p < 0.001), whereas serum and plasma levels of ANG were comparable and significantly correlated (r = 0.8; p < 0.01). Compared to normal controls (1.3 +/- 0.09 pg), serum levels of VEGF corrected for the peripheral blood platelet count (VEGF/10(6) platelets, VEGF(PLT)) were elevated in patients with refractory anemia (RA; 3.1 +/- 0.8 pg, p < 0.01), and reached maximal values in patients with advanced stage MDS (RAEB, RAEB-t) (3.5 +/- 0.6 pg, p < 0.001), de novo AML (3.6 +/- 1.1 pg, p < 0.05), and chronic myelomonocytic leukemia (CMML; 3.7 +/- 0.9 pg; p < 0.001). Levels of soluble ANG were elevated in RA (351 +/- 25.7 ng/ml, p < 0.001), in RAEB/RAEB-t (402 +/- 17.9 ng/ml; p < 0.001), in CMML (413.8 +/- 29.5 ng/ml; p < 0.001), and in patients with AML (305.1 +/- 17.1 ng/ml; p < 0.01, controls 255.4 +/- 8.1 ng/ml). Serum bFGF was neither elevated in MDS nor in AML patients. These results suggest that VEGF(PLT) is a marker of disease progression in MDS. Moreover, we show for the first time that elevated blood levels of ANG can be found in patients with myeloid malignancies, suggesting a role of ANG in the pathogenesis of these diseases.     

Measurement of free and complexed soluble vascular endothelial growth factor receptor, Flt-1, in fluid samples: development and application of two new immunoassays

Vascular endothelial growth factor (VEGF) mediates endothelial cell mitogenesis and enhances vascular permeability. VEGF interacts with the endothelium via two membrane-spanning receptors, fms-like tyrosine kinase (Flt)-1 and kinase domain receptor. A soluble form of Flt-1 (sFlt-1) was isolated from endothelial cell media; however, its biological significance is still unknown, with limited data on plasma sFlt-1 levels in disease states. We have developed two new ELISAs for detecting free and VEGF-complexed sFlt-1, which were tested in accordance with standard validation and assessment methodologies employed in commercial settings. The intra-and inter-assay coefficients of variation are <5% and 10% respectively, and results are highly reproducible. Applying these ELISAs in a clinical setting, we measured levels of VEGF, free and complexed sFlt-1 in citrated plasma from 40 patients with cardiovascular disease and 40 healthy controls. Median (interquartile range) plasma levels of VEGF in patients were significantly greater than controls [403 pg/ml (158--925 pg/ml) versus 113 pg/ml (33--231 pg/ml), P< or =0.05]. Free sFlt-1 was significantly lower in patients compared with controls [8 ng/ml (2--22 ng/ml) versus 21 ng/ml (10--73 ng/ml), P< or =0.05]. There was no significant difference in the levels of complexed sFlt-1 between the two groups. Plasma levels of VEGF-complexed sFlt-1 are minimal, despite the presence of excess free sFlt-1. Thus unbound plasma VEGF detected by ELISA may represent the majority of circulating VEGF, and justifies the measurement of plasma VEGF as an indicator of circulating VEGF levels. Furthermore, these results suggest that circulating sFlt-1 may serve as a selective inhibitor of VEGF activity, and that this regulatory mechanism may be altered by pathological conditions.     

Effects of oxidative stress on endothelial function after a high-fat meal

Postprandial lipaemia is known to cause endothelial dysfunction, but its underlying mechanism is still under debate. The present study was undertaken to investigate the effects of postprandial lipaemia on endothelial dysfunction and oxidative stress. We measured plasma glutathione peroxidase (GSH-Px), an antioxidant enzyme, and the urinary excretion of 8-epi-prostaglandin F2alpha (8-PGF2alpha), a free radical-catalysed product from the oxidative modification of arachidonic acid, in 16 healthy subjects (mean age, 30 +/- 5 years) without major coronary risk factors. Plasma high-sensitive C-reactive protein, soluble intercellular cell-adhesion molecule-1 and vascular cell-adhesion molecule-1 were also measured. High-resolution ultrasound was used to assess the flow-mediated vasodilatation (FMD) of the brachial artery. Blood and urine samples were collected before and 2, 4 and 6 h after a standard high-fat meal (3677 J, containing 50 g of fat). Serum triacylglycerol (triglyceride) increased and FMD decreased significantly after a high-fat meal. Plasma GSH-Px significantly decreased from 27.2 +/- 12.3 microg/ml to 25.7 +/- 11.8 microg/ml (P=0.022) 2 h after the meal, and urinary excretion of 8-PGF2alpha significantly increased from 1286 +/- 1401 pg/mg of creatinine to 2197 +/- 1343 pg/mg of creatinine (P=0.014) at 4 h after the meal. However, there were no significant changes in the levels of high-sensitive C-reactive protein and adhesion molecules after a high-fat meal. In conclusion, endothelial dysfunction was observed after consuming a high-fat meal and is associated with augmented oxidative stress manifested by the depletion of serum antioxidant enzymes and increased excretion of oxidative modification products.     

Serum levels of endostatin, vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in patients with acute myocardial infarction undergoing early reperfusion therapy

Angiogenesis is controlled by anti-angiogenic factors as well as by angiogenic factors, such as VEGF (vascular endothelial growth factor) and HGF (hepatocyte growth factor). Endostatin, a potent endogenous angiogenesis inhibitor, is known to inhibit endothelial proliferation and suppress tumour growth. However, to date, little is known about the pathophysiology of endostatin in ischaemia/reperfusion. To investigate the mechanisms of angiogenesis induced by myocardial ischaemia/reperfusion in more detail, we studied the circulating levels of endostatin, VEGF and HGF in 17 patients with acute myocardial infarction, who underwent early reperfusion therapy. In all patients, serum endostatin, VEGF and HGF levels before reperfusion were increased significantly compared with those in 17 control subjects (endostatin, 49.2+/-11.7 ng/ml, but not detectable in controls; VEGF, 685.6+/-150.3 pg/ml compared with 173.7+/-33.6 pg/ml; HGF, 3638+/-1285 pg/ml compared with 59+/-13 pg/ml; values are means+/-S.E.M.). After reperfusion, the serum endostatin and VEGF levels decreased significantly, but still remained higher than those in control subjects (endostatin, 19.6+/-7.0 ng/ml; VEGF, 284.2+/-90.2 pg/ml). In contrast, serum HGF levels increased significantly (15 146+/-2230 pg/ml) after reperfusion. These data indicated that serum levels of endostatin changed in parallel with those of VEGF in response to myocardial ischaemia/reperfusion, and the marked increase in serum HGF levels after reperfusion seemed to be, at least in part, due to heparin administration. Our data offer a possible anti-endostatin therapy in patients with acute myocardial infarction to facilitate collateral vessel formation.     

Effect of endogenous estrogen on endothelial function in women with coronary heart disease and its mechanism

BACKGROUND: Estrogen promotes and modulates vascular endothelial function, which may be protective against development of atherosclerosis. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, has been reported to be associated with the impairment of vascular endothelial function. Recent studies suggested estrogen replacement therapy lowers plasma concentrations of ADMA in healthy postmenopausal women. However, the relation between endogenous estrogen and ADMA and their effect on endothelial function in patients with coronary heart disease (CHD) remains unclear. METHODS: Flow-mediated dilatation (FMD) and nitroglycerin-induced dilatation (NID) of the brachial arteries were detected by using high-resolution ultrasound in 33 women with CHD and 17 healthy controls. Plasma estradiol, ADMA, and lipid concentrations were also measured in all subjects. RESULTS: In comparison with control group, FMD and NID were significantly decreased in the CHD group (1.73 +/- 1.26% vs. 5.37 +/- 3.20%, p < 0.001 and 12.38 +/- 6.70% vs. 20.79 +/- 7.57%, p < 0.01, respectively). Plasma estradiol concentrations in the CHD group were lower than in controls (27.80 +/- 12.28 vs. 43.83 +/- 14.30 pg/ml, p < 0.01), whereas ADMA concentrations in the CHD group were higher than in controls (3.39 +/- 1.07 vs. 1.31 +/- 0.69 micromol/l, p < 0.001). Pearson correlation analysis determined that plasma estradiol concentrations were associated with FMD, NID, age, systolic pressure, diastolic pressure and ADMA (r = 0.610, p < 0.01; r = 0.392, p < 0.01; r = -0.589, p < 0.01; r= -0.364, p < 0.01; r = -0.350, p < 0.05; r = -0.553, p < 0.01; respectively). Multiple linear stepwise regression analysis revealed that plasma estradiol concentrations was independently positively correlated with FMD (p < 0.005) and negatively correlated with ADMA (p < 0.05). CONCLUSIONS: Both FMD and NID are impaired in women with CHD. The decrease of endogenous estrogen concentrations and the increase of ADMA concentrations may involve the endothelial dysfunction in women with CHD.     

LDL-apheresis up-regulates VEGF and IGF-I in patients with ischemic limb

Although it is known that LDL-apheresis improves ischemic limb seen in patients with peripheral arterial occlusive disease (PAOD), the underlying mechanism(s) still remains unknown. We studied whether vascular endothelial growth factor (VEGF) and/or insulin-like growth factor-I (IGF-I) levels correlated with improvement of ischemic limbs after LDL-apheresis. Sixteen patients with PAOD (13 men, 3 women) were enrolled in our study. LDL-apheresis was performed 10 times (treated plasma 3,000 ml) for 5 weeks. Serum level of VEGF significantly increased from 262 +/- 171 pg/ml to 306 +/- 165 pg/ml before and after LDL-apheresis (P < 0.05). This value further increased up to 441 +/- 175 pg/ml 3 months after the end of this therapy (P < 0.01, compared with the basal value and P < 0.05, compared with the value at the end of 10-times session). Increased levels of VEGF paralleled increases in the ankle-brachial pressure index (ABI). After 10-times therapy, IGF-I significantly decreased (P < 0.05), but increased over the basal value 3 months after this therapy. Plasma fibrinogen statistically decreased and remained low for 3 months. The favorable effects of LDL-apheresis may be ascribed to up-regulation of VEGF and IGF-I associated with decreased fibrinogen levels.     

三氧化二砷下调慢性髓系白血病骨髓细胞VEGF的表达

为了研究三氧化二砷 (As2 O3 )对慢性髓系白血病 (CML)各期患者血管内皮生长因子 (VEGF)表达水平的影响 ,采用酶联免疫吸附法 (ELISA)检测正常人和CML慢性期、加速期和急变期患者骨髓细胞经As2 O3 作用前、后培养上清液VEGF水平的变化。结果发现 ,2 0例慢性期、8例加速期和 7例急变期患者骨髓细胞培养上清液VEGF水平分别为 6 4 9.16± 382 .2 0 pg/ml,5 6 0 .2 7± 4 0 9.14 pg/ml和 5 87.18± 4 15 .2 8pg/ml,明显高于对照组的15 2 .16± 15 0 .0 9pg/ml(P <0 .0 1) ,但不同病程阶段的CML患者间VEGF水平的差别无统计学意义。慢性期、加速期及急变期CML患者骨髓细胞经浓度为 5× 10 -6mol/L的As2 O3 处理 72小时后 ,VEGF表达水平均出现明显下调 ,分别为 396 .6 6± 2 5 7.4 7pg/ml,36 3.4 2± 2 39.85pg/ml和 4 0 7.4 7± 2 19.38pg/ml,与未加As2 O3 组比较差别显著 (P <0 0 5 )。结论 :VEGF异常增高可能在CML整个发病过程中都发挥一定作用 ,As2 O3 下调白血病细胞VEGF表达可能是其抗肿瘤作用的机制之一     

In vivo platelet activation is responsible for enhanced vascular endothelial growth factor levels in hypertensive patients

BACKGROUND: Essential hypertension may be a consequence of an abnormal regulation of vascular endothelial growth factor (VEGF). In vivo activation of platelets does result in the release of VEGF. Thus, we investigated whether VEGF production in hypertensive patients is related to in vivo platelet activation, and whether it may be modified by aspirin treatment. METHODS: Plasma VEGF, soluble (s)P-selectin and thrombin-anti-thrombin complex (TATc) were analyzed in 80 patients with therapeutically controlled essential hypertension and 40 age and sex-matched healthy normotensive controls. The effects of a 6-month treatment with aspirin 100 mg/day on VEGF levels of 20 hypertensive patients were also studied. RESULTS: Plasma VEGF (p<0.0001), sP-selectin (p=0.01) and TATc (p=0.02) levels were higher in hypertensives compared to controls. Multivariate analysis including age, sex, risk factors, cardiovascular disease, anti-hypertensive treatment, sP-selectin and TATc showed that only sP-selectin was an independent predictor of VEGF (beta=0.40, p<0.03). Aspirin treated hypertensives showed a significant reduction of sP-selectin (-26%, p<0.01) and VEGF (-33%, p<0.01) levels. Moreover, the reduction of plasma VEGF levels directly correlated with that of sP-selectin (Rho=0.46, p=0.04). CONCLUSIONS: In vivo activation of platelets in hypertensive patients is responsible for enhanced circulating VEGF levels, which are significantly lowered by aspirin treatment.     

Non-invasive detection of acute renal allograft rejection by measurement of vascular endothelial growth factor in urine

Urinary vascular endothelial growth factor (VEGF) was determined by enzyme-linked immunosorbent assay in 199 renal allograft recipients and 80 healthy controls. Urinary VEGF level did not change significantly during the first 8 weeks after transplantation in 119 patients with stable renal function and there were no abnormal histological findings (No-AR). In 67 patients with acute rejection, urinary VEGF was significantly higher (28.57 +/- 6.21 pg/micromol creatinine) than in the No-AR patients (3.05 +/- 0.45 pg/micromol creatinine) and healthy controls (2.87 +/- 0.35 pg/micromol creatinine). At a cut-off point of 3.26 pg/micromol creatinine, sensitivity and specificity for diagnosis of acute rejection were 86.6 and 71.4%, respectively. The 13 patients with subclinical rejection excreted urinary VEGF (16.14 +/- 4.09 pg/micromol creatinine) at a significantly higher level than No-AR patients (3.05 +/- 0.45 pg/micromol creatinine). At a cut-off point of 4.69 pg/micromol creatinine, sensitivity and specificity for diagnosis of subclinical rejection were 84.6 and 79.8%, respectively. In conclusion, monitoring VEGF in urine might offer a new non-invasive way to detect acute and subclinical rejection in renal transplant recipients.     

Role of vascular endothelial cell growth factor in Ovarian Hyperstimulation Syndrome.

Controlled ovarian hyperstimulation with gonadotropins is followed by Ovarian Hyperstimulation Syndrome (OHSS) in some women. An unidentified capillary permeability factor from the ovary has been implicated, and vascular endothelial cell growth/permeability factor (VEGF) is a candidate protein. Follicular fluids (FF) from 80 women who received hormonal induction for infertility were studied. FFs were grouped according to oocyte production, from group I (0-7 oocytes) through group IV (23-31 oocytes). Group IV was comprised of four women with the most severe symptoms of OHSS. Endothelial cell (EC) permeability induced by the individual FF was highly correlated to oocytes produced (r2 = 0.73, P < 0.001). Group IV FF stimulated a 63+/-4% greater permeability than FF from group I patients (P < 0. 01), reversed 98% by anti-VEGF antibody. Group IV fluids contained the VEGF165 isoform and significantly greater concentrations of VEGF as compared with group I (1,105+/-87 pg/ml vs. 353+/-28 pg/ml, P < 0. 05). Significant cytoskeletal rearrangement of F-actin into stress fibers and a destruction of ZO-1 tight junction protein alignment was caused by group IV FF, mediated in part by nitric oxide. These mechanisms, which lead to increased EC permeability, were reversed by the VEGF antibody. Our results indicate that VEGF is the FF factor responsible for increased vascular permeability, thereby contributing to the pathogenesis of OHSS.     

Functional significance of vascular endothelial growth factor and its receptor (receptor-1) in various lung cancer types

OBJECTIVES: VEGF is one of the key factors in tumor angiogenesis that may be involved in tumor growth and metastasis. VEGF receptor, a naturally occurring soluble form of the VEGFR-1 (sVEGFR-1. flt-1), is produced by endothelial cells by differential splicing of the flt-1 gene, and is a negative counterpart of the VEGF signaling pathway. DESIGN AND METHODS: We investigated the levels of VEGF and sVEGFR-1, a known intrinsic inhibitor of VEGF, in 42 patients with various types of lung cancers before beginning treatment and 18 healthy subjects. RESULTS: Serum sVEGFR-1 levels (mean +/- SD; pg/ml) were 465.17 +/- 158.34 in patients and were significantly higher than those of the healthy subjects (156.39 +/- 89.17) (P < 0.0001). Serum VEGF levels of patients (449.48 +/- 175.54 pg/ml) were significantly higher in patients than in healthy subjects (77.06 +/- 47.26 pg/ml) (P < 0.0001). CONCLUSIONS: We conclude that increased sVEGFR-1 and VEGF levels are important parameters in lung cancers.     

血清VEGF的表达与肌营养不良症的关系

目的检测肌营养不良症患者的血清血管生长因子（VEGF）水平,鉴定其是否与肌营养不良症的疾病发展有关。方法对46例肌营养不良患者,其中32例Duchenne肌营养不良症（DMD）、9例Becker肌营养不良症（BMD）、5例强直性肌营养不良症（DM）患者的血清VEGF水平进行检测。15例健康人和8例疾病患者为对照组。结果DMD患者血清VEGF为（274．7±2．52）pg／ml,BMD患者的为（358．8±9．64）pg／ml,DM患者为（165．0±6．34）pg／ml,而健康对照组为（148．3±2．91）pg/ml,疾病对照组为（153．7±5．42）pg／ml。与DM组和对照组相比,BMD的VEGF水平显著提高。而DMD组中卧床的患者相对于坐轮椅的DMD、DM组和对照组则VEGF水平显著升高。结论VEGF可以反映肌肉组织低氧和／或缺血状况,并且与DMD和BMD患者的疾病发展过程有关。     

Effect of lowering tumour necrosis factor-alpha on vascular endothelial function in Type II diabetes

Tumour necrosis factor-alpha (TNF alpha) is a mediator of reactive oxygen species, which are implicated in endothelial dysfunction and atherosclerosis. Type II diabetes is associated with endothelial dysfunction and elevated circulating TNF alpha. We hypothesized that reducing serum levels of TNFalpha, using pentoxifylline, would improve endothelial function. Thirteen subjects [age 58+/-2 (S.E.M.) years] with Type II diabetes (disease duration 74+/-13 months) undertook a randomized, crossover study of 8 weeks pentoxifylline and 8 weeks placebo. Endothelium-dependent and-independent vasodilation in resistance arteries was assessed via bilateral forearm venous occlusion plethysmography during intra-brachial infusions of acetylcholine (ACh), sodium nitroprusside (SNP) and N(G)-monomethyl-L-arginine (L-NMMA). High-resolution ultrasound of the brachial artery in response to ischaemia was used to determine endothelium-dependent conduit vessel flow-mediated dilation (FMD), and endothelium-independent conduit function was assessed by sublingual administration of glyceryl trinitrate (GTN). Serum concentrations of TNF alpha were also determined. Pentoxifylline lowered serum TNF alpha from 4.1+/-0.7 to 2.9+/-0.6 pg x ml(-1) (P=0.001). Forearm blood flow (FBF) responses at each dose of ACh did not differ with treatment (P=0.4). Similarly, FBF responses to SNP (P=0.8) and L-NMMA (P=0.2) did not differ. There was also no significant difference in brachial artery diameter during FMD (P=0.2) or GTN administration (P=0.06). Despite lowering serum TNF alpha concentration, pentoxifylline at a dose of 400 mg three times a day for 8 weeks did not improve vascular function in either conduit or resistance vessels in this group of Type II diabetic subjects.     

Vascular ophthalmological side effects associated with antiviral therapy for chronic hepatitis C are related to vascular endothelial growth factor levels

We have screened for the incidence of vascular ophthalmological side effects (VOSE) in chronic hepatitis C (CHC) patients undergoing pegylated interferon (peg-IFN) plus ribavirin (RBV) therapy and sought evidence for angiogenesis activation. Thirty-four CHC patients were prospectively evaluated (18 patients with 180 microg/week of peg-IFN-alpha2a plus 800mg/day of RBV and 16 with 1.5 microg/kg/week of peg-IFN-alpha2b plus 800-1,200mg/day of RBV). Complete ophthalmological evaluation and serum vascular endothelial growth factor (VEGF) levels were assessed before and at the end of therapy. Thirteen patients (38.2%) developed VOSE, eight (23.5%) featured subconjunctival haemorrhage, and five (14.7%) had evidence of retinopathy - all were unrelated to age, sex, genotype, the type of antiviral schedule used and response to therapy. At the end of treatment, the VOSE group had significantly higher serum VEGF levels than the group of patients without detectable side effects (median 281 [range 106-386] vs 117 [83-225] pg/ml, P=0.05). These differences increased when VEGF values were corrected by platelet count. In the VOSE group, baseline VEGF and VEGF/platelet values were also significantly higher (164 [55-260] vs 64 [21-172] pg/ml, P=0.046; and 0.920 [0.217-1.543] vs 0.320 [0.100-0.661] pg/10(6) platelets, P=0.024, respectively]. In a multivariate model VEGF/platelet values at end of treatment and hepatic fibrosis stage were the only predictors of VOSE development. In 3 out of 13 patients visual acuity was affected and 2 had residual lesions in the follow-up. In this exploratory study, antiviral therapy of CHC frequently induces VOSE, apparently through an activation of angiogenesis.     

Vascular endothelial functions,carotid intima-media thickness,and soluble CD40 ligand levels in dipper and nondipper essential hypertensive patients

OBJECTIVE: The lack of nocturnal decline in blood pressure (BP) is associated with an increase in cardiovascular events. Soluble CD40 ligand (sCD40L) is involved in the pathogenesis of risk factor-related vascular damage. The purpose of this study was to examine the relationship between vascular endothelial functions, carotid intima-media thickness (cIMT), plasma sCD40L levels and circadian BP profile in patients with essential hypertension. MATERIAL AND METHODS: The study population consisted of 81 essential hypertensive out-patients. BP dipping was defined as a night-to-day systolic and diastolic decrease >/=10%. Forty-seven dipper and 34 nondipper patients were compared. High sensitivity C-reactive protein (hs-CRP), sCD40L and urinary albumin were measured. Brachial artery flow-mediated dilatation (FMD) and cIMT was compared between the groups. RESULTS: sCD40L level (3.28 +/- 2.08 and 2.30 +/- 1.99 ng/ml, respectively, P = 0.036) and urinary albumin concentration (36.7 +/- 20.1 and 23 +/- 29.7 mg/l, respectively, P < 0.0001) were higher in nondippers than in dippers. Serum hs-CRP levels were not significantly different. FMD was found higher in dippers than nondippers (11.8 +/- 3.9% and 6.6 +/- 2.2%, respectively, P < 0.0001). The average cIMT was significantly higher in nondippers than dippers (0.928 +/- 0.060 Vs. 0.734 +/- 0.134 mm; P < 0.0001). CONCLUSIONS: Nondipper patern has an additional negative effect on endothelial functions in hypertensive patients. Nondippers have enhanced sCD40L levels, which may contribute to their increased susceptibility to develop vascular damage.     

Circadian variation in vascular tone and endothelial cell function in normal males

The existence of circadian rhythms in the time of onset of acute cardiovascular events has been described previously. This report describes the circadian variation in endothelial cell products, such as nitric oxide (NO) and endothelin-1 (ET-1) levels, and endothelium-dependent and -independent vasodilation in normal males. Plasma ET-1 and NO were measured every 4 h in nine subjects (20-41 years old) over a 24 h period. Endothelium-dependent and -independent vascular responses were measured in the forearm skin every 4 h using laser Doppler imaging after iontophoresis of increasing doses of acetylcholine (ACh) and sodium nitroprusside respectively. A statistically significant circadian variation was demonstrated for the mean ACh response (P=0.0001, ANOVA). The peak response [in arbitrary perfusion units (AU)] occurred at 16.00 hours (8.90+/-1.91 AU) and the lowest response at 08.00 hours (4.57+/-0.66 AU). A significant circadian variation was also seen for the highest dose of sodium nitroprusside (P=0.036, ANOVA), the peak occurred at 16.00 hours (3.97+/-1.80 AU), and the lowest at 04.00 hours (2.62+/-0.58 AU) and 08.00 hours (2.58+/-1.16 AU). There was a significant circadian variation in the ET-1 levels (P=0.04) with two peaks, one at 20.00 hours (0.80+/-0.28 pg/ml) and the other at 08.00 hours (0.84+/-0.15 pg/ml). The lowest value occurred at 16.00 hours (0.61+/-0.24 pg/ml). There was also a borderline trend for a circadian variation in NO levels (P=0.06), with higher levels at 20.00 hours (15.53+/-8.42 micromol/l), and low levels at 04.00 hours (10.87+/-4.70 micromol/l) and 08.00 hours (9.82+/-3.15 micromol/l). ACh responses were significantly correlated with ET-1 (r=-0.3, P=0.02) and NO (r=0.30, P=0.02) levels. Our findings suggest that endothelial activity has a circadian variation with attenuation in the morning. These circadian variations in endothelial activity might play an important role in the occurrence of acute cardiovascular events at this time, which are precipitated through the interplay between ET-1, NO and vascular function.     

Plasma vascular endothelial growth factor, angiopoietin-1, and angiopoietin-2 in diabetes: implications for cardiovascular risk and effects of multifactorial intervention

OBJECTIVE: Vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-1 and Ang-2 are mediators of angiogenesis. More recent data suggest that the balance between these growth factors may affect vascular endothelial integrity. Because diabetes is closely associated with endothelial perturbation, we studied plasma levels of these angiogenic growth factors in patients with diabetes; their relationship with glycemia, inflammation, and endothelial damage/dysfunction; and the effect of intensified cardiovascular risk management. RESEARCH DESIGN AND METHODS: We measured plasma VEGF, Ang-1, and Ang-2 alongside plasma von Willebrand factor (vWf) and urine albumin-to-creatinine ratio (marking endothelial damage/dysfunction) and interleukin (IL)-6 in 94 patients (38 with overt cardiovascular disease [CVD]) with diabetes and 34 normal control subjects. RESULTS: Plasma vWf (P=0.009), IL-6 (P <0.001), VEGF (P=0.001), and Ang-2 (P=0.001), but not Ang-1 (P=0.635), were higher in diabetic patients with and without CVD than in control subjects. On multivariate analysis, HbA1c was an independent predictor of plasma VEGF (P=0.032) and Ang-2 (P=0.015). Of the 94 patients, a subgroup of 33 patients with and 31 patients without CVD participated in a year of intensified cardiovascular risk management. HbA1c and LDL cholesterol reduced significantly with treatment, along with associated reductions in plasma vWf and VEGF in both groups (P <0.001). Ang-2 decreased (P <0.001) only in patients without CVD. There were no significant changes in plasma IL-6 levels in both groups. CONCLUSIONS: Plasma Ang-2 (but not Ang-1), like VEGF levels, are selectively elevated in patients with diabetes and are associated with indexes of endothelial damage/dysfunction, regardless of vascular disease. Intensive multifactorial intervention is associated with reductions in plasma VEGF, vWf, and (in patients without CVD) Ang-2 levels, possibly reflecting an improved vascular profile with treatment.     

脑源性神经营养因子(BDNF)在多发性骨髓瘤患者血浆中表达增高及其意义的初步研究

为了研究多发性骨髓瘤 (MM)患者血浆中脑源性神经营养因子 (BDNF)、血管内皮细胞生长因子 (VEGF)的表达情况和BDNF与血管新生的关系 ,初步探讨BDNF在MM的发生与发展中的潜在作用 ,用酶联免疫吸附试验 (ELISA)测定MM患者与健康体检者血浆BDNF和VEGF的浓度 ;采用MTT法观察BDNF对脐静脉内皮细胞(HUVEC)增殖的作用 ;用改良的Boyden小室法和体外小管形成实验等体外血管新生模型观察BDNF对HUVEC迁移和形成血管通道的影响 ;采用鸡胚尿囊膜血管生成实验和小鼠matrigelplug方法观察BDNF对体内血管新生的影响。结果表明 :患者血浆BDNF浓度为 (4.2 2± 0 .6 4 )ng ml,与健康体检者 (2 .0 3± 0 .38)ng ml相比 ,差异有显著性意义 (P =0 .0 10 ) ;患者血浆VEGF浓度为 (79.35± 13.2 5 ) pg ml,与健康体检者 (34.4 1± 1.78)pg ml相比 ,差异有显著性意义 (P =0 .0 0 6 )。BDNF与VEGF水平间存在着相关性 (r =0 .4 30 ,P =0 .0 2 5 )。BDNF对HUVEC的增殖没有显著作用 ,但可明显促进HUVEC的迁移和管状结构形成 ;同时可促进鸡胚尿囊膜血管生成和matrigelplug中血管新生。结论 :MM患者血浆BDNF和VEGF显著增高 ,BDNF在体内外均具有明显的促血管新生效应 ,在MM的血管新生中可能起着重要作用。     

Impairment of secretin release in celiac sprue.

Plasma secretin concentrations and pH in the second portion of duodenum were measured in the fasting state and during duodenal infusion of HCl in five patients with untreated celiac sprue, five celiac sprue patients after gluten-free diets, and five normal subjects. Mean fasting plasma secretin concentrations were insignificantly lower in untreated sprue patients (4.1 +/- 1.4 pg/ml) than in normal subjects (5.7 +/- 0.59 pg/ml). During 30-min intraduodenal infusions of 0.1 N HCl at 0.20 mEqH+/min, mean plasma secretin concentrations were significantly lower in untreated sprue patients (5.8 +/- 1.8 pg/ml) than in normal subjects (25.4 +/- 1.60 pg/ml, P less than 0.01). The increases in mean secretin concentrations over fasting were 2.1 +/- 0.82 pg/ml in untreated sprue patients compared to 19.7 +/- 1.47 pg/ml in normal subjects (P less than 0.01), a ninefold difference. The results indicate that endogenous release of secretin in response to duodenal acidification is impaired in patients with celiac sprue.