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Sample records for cerebral vascular endothelial

  1. Vascular endothelial growth factor induced angiogenesis following focal cerebral ischemia/reperfusion injury in rabbits

    Institute of Scientific and Technical Information of China (English)

    Huaijun Liu; Jiping Yang; Fenghai Liu; Qiang Zhang; Hui Li

    2006-01-01

    BACKGROUND: Therapeutic angiogenesis has opened up new pathway for the treatment of ischemic cerebrovascular disease in recent years. The exploration of the effect of vascular endothelial growth factor (VEGF) on inducing angiogenesis following ischemia/reperfusion injury can provide better help for the long-term treatment of cerebrovascular disease in clinic.OBJECTIVE: To observe the effect of VEGF on inducing angiogenesis following focal cerebral ischemia/reperfusion injury in rabbits through the angiogenesis of microvessels reflected by the expression of the factors of vascular pseudohemophilia.DESIGN: A randomized controlled animal trial.SETTING: Department of Medical Imaging, Second Hospital of Hebei Medical University.MATERIALS: Sixty-five healthy male New Zealand rabbits of clean degree, weighing (2.6±0.2) kg, aged4.5-5 months, were used. The polyclonal antibody against vascular pseudohemophilia (Beijing Zhongshan Company), recombinant VEGF165 (Peprotech Company, USA), biotinylated second antibody and ABC compound (Wuhan Boster Company) were applied.METHODS: The experiments were carried out in the Laboratory of Neuromolecular Imaging and Neuropathy,Second Hospital of Hebei Medical University from May to August in 2005. ① The rabbits were randomly divided into three groups: sham-operated group (n=15), control group (n=25) and VEGF-treated group(n=25). In the control group and VEGF-treated group, models were established by middle cerebral artery occlusion (MCAO) induced focal cerebral ischemia/reperfusion. In the VEGF-treated group, VEGF165(2.5 mg/L) was stereotactically injected into the surrounding regions of the infarcted sites immediately after the 2-hour ischemia/reperfusion; Saline of the same dosage was injected in the control group. But the rabobserved on the 3rd, 7th, 14th, 28th and 70th days of the experiment respectively, 3 rabbits in the sham-operated group and 5 in the control group and VEGF-treated group were observed at each time point. The

  2. Response of the sensorimotor cortex of cerebral palsy rats receiving transplantation of vascular endothelial growth factor 165-transfected neural stem cells

    Institute of Scientific and Technical Information of China (English)

    Jielu Tan; Xiangrong Zheng; Shanshan Zhang; Yujia Yang; Xia Wang; Xiaohe Yu; Le Zhong

    2014-01-01

    Neural stem cells are characterized by the ability to differentiate and stably express exogenous ge-nes. Vascular endothelial growth factor plays a role in protecting local blood vessels and neurons of newborn rats with hypoxic-ischemic encephalopathy. Transplantation of vascular endothelial growth factor-transfected neural stem cells may be neuroprotective in rats with cerebral palsy. In this study, 7-day-old Sprague-Dawley rats were divided into ifve groups: (1) sham operation (control), (2) cerebral palsy model alone or with (3) phosphate-buffered saline, (4) vascular en-dothelial growth factor 165 + neural stem cells, or (5) neural stem cells alone. hTe cerebral palsy model was established by ligating the letf common carotid artery followed by exposure to hypox-ia. Phosphate-buffered saline, vascular endothelial growth factor + neural stem cells, and neural stem cells alone were administered into the sensorimotor cortex using the stereotaxic instrument and microsyringe. Atfer transplantation, the radial-arm water maze test and holding test were performed. Immunohistochemistry for vascular endothelial growth factor and histology using hematoxylin-eosin were performed on cerebral cortex. Results revealed that the number of vas-cular endothelial growth factor-positive cells in cerebral palsy rats transplanted with vascular endothelial growth factor-transfected neural stem cells was increased, the time for ifnding water and the ifnding repetitions were reduced, the holding time was prolonged, and the degree of cell degeneration or necrosis was reduced. hTese ifndings indicate that the transplantation of vascu-lar endothelial growth factor-transfected neural stem cells alleviates brain damage and cognitive deifcits, and is neuroprotective in neonatal rats with hypoxia ischemic-mediated cerebral palsy.

  3. Response of the sensorimotor cortex of cerebral palsy rats receiving transplantation of vascular endothelial growth factor 165-transfected neural stem cells.

    Science.gov (United States)

    Tan, Jielu; Zheng, Xiangrong; Zhang, Shanshan; Yang, Yujia; Wang, Xia; Yu, Xiaohe; Zhong, Le

    2014-10-01

    Neural stem cells are characterized by the ability to differentiate and stably express exogenous ge-nes. Vascular endothelial growth factor plays a role in protecting local blood vessels and neurons of newborn rats with hypoxic-ischemic encephalopathy. Transplantation of vascular endothelial growth factor-transfected neural stem cells may be neuroprotective in rats with cerebral palsy. In this study, 7-day-old Sprague-Dawley rats were divided into five groups: (1) sham operation (control), (2) cerebral palsy model alone or with (3) phosphate-buffered saline, (4) vascular endothelial growth factor 165 + neural stem cells, or (5) neural stem cells alone. The cerebral palsy model was established by ligating the left common carotid artery followed by exposure to hypoxia. Phosphate-buffered saline, vascular endothelial growth factor + neural stem cells, and neural stem cells alone were administered into the sensorimotor cortex using the stereotaxic instrument and microsyringe. After transplantation, the radial-arm water maze test and holding test were performed. Immunohistochemistry for vascular endothelial growth factor and histology using hematoxylin-eosin were performed on cerebral cortex. Results revealed that the number of vascular endothelial growth factor-positive cells in cerebral palsy rats transplanted with vascular endothelial growth factor-transfected neural stem cells was increased, the time for finding water and the finding repetitions were reduced, the holding time was prolonged, and the degree of cell degeneration or necrosis was reduced. These findings indicate that the transplantation of vascular endothelial growth factor-transfected neural stem cells alleviates brain damage and cognitive deficits, and is neuroprotective in neonatal rats with hypoxia ischemic-mediated cerebral palsy.

  4. Vascular endothelial growth factor improves recovery of sensorimotor and cognitive deficits after focal cerebral ischemia in the rat.

    Science.gov (United States)

    Wang, Yaoming; Galvan, Veronica; Gorostiza, Olivia; Ataie, Marina; Jin, Kunlin; Greenberg, David A

    2006-10-18

    Vascular endothelial growth factor (VEGF) is an angiogenesis factor with neurotrophic, neuroprotective and neuroproliferative effects. Depending on the dose, route and time of administration in relation to focal cerebral ischemia, VEGF can improve histological outcome and sensorimotor function in rodents. However, VEGF also increases vascular permeability, which can lead to brain edema and exacerbate ischemic brain injury. Thus, although VEGF is a candidate therapeutic for stroke and other ischemic disorders, its benefit relative to risk is uncertain. Considering that functional rather than histological measures of outcome are probably most relevant to therapeutic prospects for human stroke, we investigated the effects of VEGF after middle cerebral artery occlusion in rats using a series of behavioral tests. We report that VEGF improves functional outcome in ischemic rats, including both sensorimotor and cognitive deficiencies.

  5. Effect of Solitaire AB stent thrombectomy on vascular endothelial function and inflammatory cytokines in patients with progressive cerebral infarction

    Institute of Scientific and Technical Information of China (English)

    Zhi-Bao Wu; Xue-Juan Han; Zi-Hao Zhang; Wen-Liang Zhang; Liang Liu

    2016-01-01

    Objective:To observe the effect of Solitaire AB stent thrombectomy on the vascular endothelial function and inflammatory cytokines in patients with progressive cerebral infarction.Methods:A total of 58 patients with progressive cerebral infarction who were admitted in our hospital were included in the study and divided into the observation group and the control group according to different treatment protocols with 29 cases in each group. The patients in the control group were given the conservation treatment. On this basis, the patients in the observation group were given Solitaire AB stent thrombectomy. The changes of vascular endothelial function and inflammatory cytokines before and after treatment in the two groups were compared.Results:ET-1 after treatment in the two groups was significantly reduced, while NO and CGRP were significantly elevated when compared with before treatment (P<0.05). ET-1 after treatment in the observation group was significantly lower than that in the control group (P<0.05), while NO and CGRP were significantly higher than those in the control group (P<0.05). S100β protein, IL-6, TNF-α, hs-CRP, and MMP-9 levels after treatment in the two groups were significantly reduced when compared with before treatment (P<0.05). The above indicators after treatment in the observation group were significantly lower than those in the control group (P<0.05). MCA and ACA blood flow velocity after treatment in the two groups were significantly elevated when compared with before treatment (P<0.05). MCA and ACA blood flow velocity after treatment in the observation group were significantly higher than those in the control group (P<0.05).Conclusions:Solitaire AB stent thrombectomy can effectively reduce the inflammatory reaction in patients with progressive cerebral infarction, and improve the vascular endothelial function and blood supply for brain tissues.

  6. Minocycline inhibits neuroinflammation and enhances vascular endothelial growth factor expression in a cerebral ischemia/reperfusion rat model

    Institute of Scientific and Technical Information of China (English)

    Zhiyou Cai; Yong Yan; Changyin Yu; Jun Zhang

    2008-01-01

    BACKGROUND: Brain ischemia involves secondary inflammation, which significantly contributes to the outcome of ischemic insults. Vascular endothelial growth factor (VEGF) may play an important role in the vascular response to cerebral ischemia, because ischemia stimulates VEGF expression in the brain, and VEGF promotes formation of new cerebral blood vessels. Minocyclinc, a tetracycline derivative, protects against cerebral ischemia and reduces inflammation, oxidative stress, and apoptosis.OBJECTIVE: To observe the influence of minocycline on VEGE interleukin-1 beta (IL-1β), and tumor necrosis factor alpha (TNF-α) expression in Wistar rats with focal cerebral ischemia/rcperfusion injury, and to study the neuroproteetion mechanism of minocycline against focal cerebral ischemia/rcpeffusion injury.DESIGN, TIME AND SETTING: Randomized, controlled experiment, which was performed in the Chongqing Key Laboratory of Neurology between March 2007 and March 2008.MATERIALS: A total of 36 female, Wistar rats underwent surgery to insert a thread into the left middle cerebral artery. Animals were randomly divided into sham-operation, minocyclinc treatment, and ischemia/reperfusion groups, with 12 rats in each group. Minocycline (Huishi Pharmaceutical Limited Company, China) was dissolved to 0.5 g/L in normal saline.METHODS: A 0.5- 1.0 cm thread was inserted into rats from the sham-operation group. Rats in the ischemia/reperfusion group underwent ischemia and reperfusion. The minocycline group received minocycline (50 mg/kg) 12 and 24 hours following ischemia and reperfusion, whereas the other groups received saline at the corresponding time points.MAIN OUTCOME MEASURES: mRNA and protein expression of IL-1β and TNF-α was measured by reverse transcriptase-polymerasc chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA), respectively. VEGF mRNA and protein expression was examined by RT-PCR, Western blot, and ELISA.RESULTS: Minocycline decreased the focal infarct

  7. [Vascular endothelial Barrier Function].

    Science.gov (United States)

    Ivanov, A N; Puchinyan, D M; Norkin, I A

    2015-01-01

    Endothelium is an important regulator of selective permeability of the vascular wall for different molecules and cells. This review summarizes current data on endothelial barrier function. Endothelial glycocalyx structure, its function and role in the molecular transport and leukocytes migration across the endothelial barrier are discussed. The mechanisms of transcellular transport of macromolecules and cell migration through endothelial cells are reviewed. Special section of this article addresses the structure and function of tight and adherens endothelial junction, as well as their importance for the regulation of paracellular transport across the endothelial barrier. Particular attention is paid to the signaling mechanism of endothelial barrier function regulation and the factors that influence on the vascular permeability.

  8. Influence of mild hypothermia on vascular endothelial growth factor and infarct volume in brain tissues after cerebral ischemia in rats

    Institute of Scientific and Technical Information of China (English)

    Fei Ye; Gangming Xi; Biyong Qin; Shifeng Wang; Chengyan Li

    2006-01-01

    BACKGROUND: It has been demonstrated that mild hypothermia has obvious protective effect on both whole and local cerebral ischemia. However, the definite mechanism is still unclear for the brain protection of mild hypothermia on cerebral edema, inhibiting inflammatory reaction, stabilizing blood brain barrier, etc.OBJECTIVE: To investigate the effect of mild hypothermia on the expression of vascular endothelial growth factor and the infarct volume after cerebral ischemia in rats, and analyze the brain protective mechanism of mild hypothermia.DESIGN: A randomized grouping and controlled animal trial.SETTING: Department of Neurology, People's Hospital of Yunyang Medical College.MATERIALS: Twenty adult male SD rats of clean degree, weighing (250±30) g, were provided by the animal experimental center, School of Medicine, Wuhan University. The kits for SP immunohistochemistry were purchased from Beijing Zhongshan Golden Bridge Biotechnology Co., Ltd.METHODS: The experiments were carried out in the laboratory of Department of Neurology, Renmen Hospital of Wuhan University from May to July 2005. ① The 20 rats were divided randomly into normal temperature group (n =10) and mild hypothermia group (n =10). Models of permanent middle cerebral artery occlusion were established with modified nylon suture embolization. The rats were assessed with the Longa standards: O point for without nerve dysfunction; 1 for mild neurological deficit (fore claws could no extend completely); 2 for moderate neurological deficit (circling towards the affected side); 3 for severe neurological deficit (tilting towards the affected side); 4 for coma and unconscious; 1 -3 points represented that models were successfully established. The rats of the normal temperature group were fed at room temperature, and those in the mild hypothermia group were induced by hypothermia from 2 hours postoperatively, and the rectal temperature was kept at 34-35 ℃ for 72 hours. ② Measurement of infarct volume

  9. 1H-magnetic resonance spectroscopy of vascular endothelial growth factor-induced neuroprotection following acute cerebral ischemia and reperfusion

    Institute of Scientific and Technical Information of China (English)

    Li Yi; Haiou Zhang; Hao Lei; Li Wei

    2008-01-01

    BACKGROUND: It has become generally accepted that measuring N-acetyI-L-aspartic acid through the use of 1H-magnetic resonance spectroscopy (1H-MRS) could be used to evaluate neuronal injury. OBJECTIVE: To study metabolic changes of N-acetyl-L-aspanic acid surrounding the acute cerebral ischcmia area following vascular endothelial growth factor (VEGF) treatment using 1H-MRS imaging, and to evaluate the neuroprotective effects of VEGE.DESIGN, TIME AND SETTING: Randomly controlled animal study, according to one-factor analysis of variance, was performed at the Shenzhen Hospital of Peking University and State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences from August 2003 to December 2005.MATERIALS: Twelve healthy, adult, Sprague Dawley rats were used to establish an ischemia/reperfusion model through the use of middle cerebral artery occlusion. The 4.7T superconducting nuclear magnetic resonance meter was provided by Brucker Company. VEGF164 was purchased from Shenzhen Jingmei Bioengineering Co., Ltd. Titus ancsthesia machine was purchased from Draeger Medical AG & Co. KG.METHODS: The rats were randomly divided into model control (n = 6) and VEGF-injected (n = 6) groups. All animals received 60-minute middle cerebral artery occlusion and 24-hour repcrfusion. Lateral cerebral ventricle injection was performed by stereotaxic technique at respective time points. The VEGF group received 0. 1 μ g/μ L VEGF (5 μL), and the model group received the same amount of normal saline, once daily for 3 days.MAIN OUTCOME MEASURES: Metabolic changes of N-acetyl-L-aspartic acid and lactic acid following cerebral ischemia and reperfusion were detected using 1H-MRS, and the ischemic volume was measured.RESULTS: Twelve rats were included in the final analysis. =H-MRS results revealed that the ischemic volume increased in the control group compared with prior to injection (P < 0.01). In the

  10. Andrographolide, a Novel NF-κB Inhibitor, Inhibits Vascular Smooth Muscle Cell Proliferation and Cerebral Endothelial Cell Inflammation

    Science.gov (United States)

    Chang, Chao-Chien; Duann, Yeh-Fang; Yen, Ting-Lin; Chen, Yu-Ying; Jayakumar, Thanasekaran; Ong, Eng-Thiam; Sheu, Joen-Rong

    2014-01-01

    Background Aberrant vascular smooth muscle cell (VSMC) proliferation and cerebral endothelial cell (CEC) dysfunction contribute significantly in the pathogenesis of cardiovascular diseases. Therefore, inhibition of these cellular events would be by candidate agents for treating these diseases. In the present study, the mechanism of anti-proliferative and anti-inflammatory effects of andrographolides, a novel nuclear factor-κB inhibitor, was investigated in VSMC and CEC cells. Methods VSMCs and CECs were isolated from rat artery and mouse brain, respectively, and cultured before experimentation. The effect of andro on platelet-derived growth factor-BB (PDGF-BB) induced VSMC cell proliferation was evaluated by cell number, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The expression of extracellular signal regulated kinase 1/2 (ERK1/2), proliferating cell nuclear antigen (PCNA), and the effects on lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) and, cyclooxygenase-2 (COX2) were detected by Western blotting. Results Andro significantly inhibited PDGF-BB (10 ng/ml) induced cell proliferation in a concentration (20-100 μM) dependent manner, which may be due to reducing the expression of ERK1/2, and by inhibiting the expression of PCNA. Andro also remarkably diminished LPS-induced iNOS and COX2 expression. Conclusions The results of this study suggested that the effects of andro against VSMCs proliferation and CECs dysfunction may represent a promising approach for treatment of vascular diseases. PMID:27122804

  11. Systemic Expression of Vascular Endothelial Growth Factor in Patients with Cerebral Cavernous Malformation Treated by Stereotactic Radiosurgery.

    Science.gov (United States)

    Park, Sang-Jin; Park, Seong-Hyun

    2016-09-01

    Increased expression of angiogenic factors, such as vascular endothelial growth factor (VEGF), is associated with the pathogenesis of cerebral cavernous malformations (CCMs). The purpose of this study was to investigate plasma levels of VEGF in normal subjects and in patients with CCM and to evaluate change in these levels following stereotactic radiosurgery (SRS). Peripheral venous blood was collected from 6 patients with CCM before SRS using Gamma Knife and at the 1 week, 1 month, 3month, and 6 month follow-up visits. Plasma VEGF levels were measured using commercially available enzyme-linked immunosorbent assay kits. Peripheral blood samples were obtained from 10 healthy volunteers as controls. Mean plasma VEGF level of 41.9 pg/mL (range, 11.7-114.9 pg/mL) in patients with CCM at baseline was higher than that of the healthy controls (29.3 pg/mL, range, 9.2-64.3 pg/mL), without significant differences between CCM patients and controls (p=0.828). Plasma VEGF level following SRS dropped to 24.6 pg/mL after 1 week, and decreased to 18.5 pg/mL after 1 month, then increased to 24.3 pg/mL after 3 months, and 32.6 pg/mL after 6 months. Two patients suffering from rebleeding after SRS showed a higher level of VEGF at 6 months after SRS than their pretreatment level. Plasma VEGF levels in patients with CCM were elevated over controls at baseline, and decreased from baseline to 1 month after SRS and increased further for up to 6 months. Theses results indicated that anti-angiogenic effect of SRS might play a role in the treatment of CCMs.

  12. VASCULAR: Inhibition of myogenic tone in rat cremaster and cerebral arteries by SKA-31, an activator of endothelial KCa2.3 and KCa3.1 channels

    OpenAIRE

    Mishra, Ramesh C.; Wulff, Heike; Hill, Michael A.; Braun, Andrew P.

    2015-01-01

    Endothelial KCa2.3 and KCa3.1 channels contribute to the regulation of myogenic tone in resistance arteries by Ca2+-mobilizing, vasodilatory hormones. To define further the functional role of these channels in distinct vascular beds, we have examined the vasodilatory actions of the KCa channel activator SKA-31 in myogenically active, rat cremaster and middle cerebral arteries. Vessels pressurized to 70 mmHg constricted by 80–100 microns (i.e. 25–45% of maximal diameter). SKA-31 (10 μM) inhibi...

  13. Early expressions of hypoxia-inducible factor 1alpha and vascular endothelial growth factor increase the neuronal plasticity of activated endogenous neural stem cells after focal cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Seung Song; Jong-Tae Park; Joo Young Na; Man-Seok Park; Jeong-Kil Lee; Min-Cheol Lee; Hyung-Seok Kim

    2014-01-01

    Endogenous neural stem cells become “activated” after neuronal injury, but the activation sequence and fate of endogenous neural stem cells in focal cerebral ischemia model are little known. We evaluated the relationships between neural stem cells and hypoxia-inducible fac-tor-1α and vascular endothelial growth factor expression in a photothromobotic rat stroke model using immunohistochemistry and western blot analysis. We also evaluated the chrono-logical changes of neural stem cells by 5-bromo-2′-deoxyuridine (BrdU) incorporation. Hypoxia-inducible factor-1α expression was initially increased from 1 hour after ischemic injury, followed by vascular endothelial growth factor expression. Hypoxia-inducible factor-1αimmunoreactivity was detected in the ipsilateral cortical neurons of the infarct core and peri-in-farct area. Vascular endothelial growth factor immunoreactivity was detected in bilateral cortex, but ipsilateral cortex staining intensity and numbers were greater than the contralateral cortex. Vascular endothelial growth factor immunoreactive cells were easily found along the peri-infarct area 12 hours after focal cerebral ischemia. The expression of nestin increased throughout the microvasculature in the ischemic core and the peri-infarct area in all experimental rats after 24 hours of ischemic injury. Nestin immunoreactivity increased in the subventricular zone during 12 hours to 3 days, and prominently increased in the ipsilateral cortex between 3-7 days. Nes-tin-labeled cells showed dual differentiation with microvessels near the infarct core and reactive astrocytes in the peri-infarct area. BrdU-labeled cells were increased gradually from day 1 in the ipsilateral subventricular zone and cortex, and numerous BrdU-labeled cells were observed in the peri-infarct area and non-lesioned cortex at 3 days. BrdU-labeled cells rather than neu-rons, were mainly co-labeled with nestin and GFAP. Early expressions of hypoxia-inducible factor-1α and

  14. Renovascular hypertension causes cerebral vascular remodeling

    Institute of Scientific and Technical Information of China (English)

    Yamei Tang; Xiangpen Li; Yi Li; Qingyu Shen; Xiaoming Rong; Ruxun Huang; Ying Peng

    2011-01-01

    Renovascular hypertensive rats (RHRs) were developed using the 2-kidney, 2-clip method. All RHRs at 10 weeks displayed high permeability of the cerebral surface blood vessels. Vascular casts of the RHRs showed that the vascular network was sparse. The arterioles of the RHRs at 10 weeks had smaller lumen diameters, but thicker vessel walls with hyalinosis formation compared with control animals. The endothelial cell membrane appeared damaged, and microthrombus formed. After ischemia, the infarction size was larger in RHRs than in control animals. These results suggest that cerebral arterioles in RHRs underwent structural remodeling. High blood pressure may aggravate the severity of brain injury in cerebral ischemia and affect the recovery of ischemia.

  15. Systemic and cerebral vascular endothelial growth factor levels increase in murine cerebral malaria along with increased Calpain and caspase activity and can be reduced by erythropoietin treatment

    DEFF Research Database (Denmark)

    Hempel, Casper; Hoyer, Nils; Kildemoes, Anna

    2014-01-01

    increased levels of VEGF in brain and plasma and decreased plasma levels of soluble VEGF receptor 2. EPO treatment normalized VEGF receptor 2 levels and reduced brain VEGF levels. Hypoxia-inducible factor (HIF)-1α was significantly upregulated whereas cerebral HIF-2α and EPO levels remained unchanged....... Furthermore, we noticed increased caspase-3 and calpain activity in terminally ill mice, as measured by protease-specific cleavage of α-spectrin and p35. In conclusion, we detected increased cerebral and systemic VEGF as well as HIF-1α, which in the brain were reduced to normal in EPO-treated mice. Also...

  16. Vascular permeability in cerebral cavernous malformations

    DEFF Research Database (Denmark)

    Mikati, Abdul G; Khanna, Omaditya; Zhang, Lingjiao;

    2015-01-01

    Patients with the familial form of cerebral cavernous malformations (CCMs) are haploinsufficient for the CCM1, CCM2, or CCM3 gene. Loss of corresponding CCM proteins increases RhoA kinase-mediated endothelial permeability in vitro, and in mouse brains in vivo. A prospective case-controlled observ......Patients with the familial form of cerebral cavernous malformations (CCMs) are haploinsufficient for the CCM1, CCM2, or CCM3 gene. Loss of corresponding CCM proteins increases RhoA kinase-mediated endothelial permeability in vitro, and in mouse brains in vivo. A prospective case......-controlled observational study investigated whether the brains of human subjects with familial CCM show vascular hyperpermeability by dynamic contrast-enhanced quantitative perfusion magnetic resonance imaging, in comparison with CCM cases without familial disease, and whether lesional or brain vascular permeability...... correlates with CCM disease activity. Permeability in white matter far (WMF) from lesions was significantly greater in familial than in sporadic cases, but was similar in CCM lesions. Permeability in WMF increased with age in sporadic patients, but not in familial cases. Patients with more aggressive...

  17. Effects of vascular endothelial growth factor on angiogenesis of the endothelial cells isolated from cavernous malformations

    Institute of Scientific and Technical Information of China (English)

    TAN YuZhen; ZHAO Yao; WANG HaiJie; ZHOU LiangFu; MAO Ying; LIU Rui; SHU Jia; WANG YongFei

    2008-01-01

    Human cerebral cavernous malformation (CM) is a common vascular malformation of the central nervous system. We have investigated the biological characteristics of CM endothelial cells and the cellular and molecular mechanisms of CM angiogenesis to offer new insights into exploring effective measures for treatment of this disease. The endothelial cells were isolated from CM tissue masses dissected during operation and expanded in vitro. Expression of VEGFR-1 and VEGFR-2 was examined with immunocytochemical staining. Proliferation, migration and tube formation of CM endothelial cells were determined using MTT, wounding and transmigration assays, and three-dimensional collagen type Ⅰ gel respectively. The endothelial cells were successfully isolated from the tissue specimens of 25 CMs dissected without dipolar electrocoagulation. The cells show the general characteristics of the vascular endothelial cells. Expression of VEGFR-1 and VEGFR-2 on the cells is higher than that on the normal cerebral microvascular endothelial cells. After treatment with VEGF, numbers of the proliferated and migrated cells, the maximal distance of cell migration and the length and area of capillary-like struc-tures formed in the three-dimensional collagen gel increase significantly. These results demonstrate that expression of VEGFR-1 and VEGFR-2 on CM endothelial cells is up-regulated. By binding to re-ceptors, VEGF may activate the downstream signaling pathways and promote proliferation, migration and tube formation of CM endothelial cells. VEGF/VEGFR signaling pathways play important regulating roles in CM angiogenesis.

  18. Systemic and cerebral vascular endothelial growth factor levels increase in murine cerebral malaria along with increased Calpain and caspase activity and can be reduced by erythropoietin treatment

    DEFF Research Database (Denmark)

    Hempel, Casper; Hoyer, Nils; Kildemoes, Anna;

    2014-01-01

    . Furthermore, we noticed increased caspase-3 and calpain activity in terminally ill mice, as measured by protease-specific cleavage of α-spectrin and p35. In conclusion, we detected increased cerebral and systemic VEGF as well as HIF-1α, which in the brain were reduced to normal in EPO-treated mice. Also...... caspase and calpain activity was reduced markedly in EPO-treated mice....

  19. Vascular permeability in cerebral cavernous malformations.

    Science.gov (United States)

    Mikati, Abdul G; Khanna, Omaditya; Zhang, Lingjiao; Girard, Romuald; Shenkar, Robert; Guo, Xiaodong; Shah, Akash; Larsson, Henrik B W; Tan, Huan; Li, Luying; Wishnoff, Matthew S; Shi, Changbin; Christoforidis, Gregory A; Awad, Issam A

    2015-10-01

    Patients with the familial form of cerebral cavernous malformations (CCMs) are haploinsufficient for the CCM1, CCM2, or CCM3 gene. Loss of corresponding CCM proteins increases RhoA kinase-mediated endothelial permeability in vitro, and in mouse brains in vivo. A prospective case-controlled observational study investigated whether the brains of human subjects with familial CCM show vascular hyperpermeability by dynamic contrast-enhanced quantitative perfusion magnetic resonance imaging, in comparison with CCM cases without familial disease, and whether lesional or brain vascular permeability correlates with CCM disease activity. Permeability in white matter far (WMF) from lesions was significantly greater in familial than in sporadic cases, but was similar in CCM lesions. Permeability in WMF increased with age in sporadic patients, but not in familial cases. Patients with more aggressive familial CCM disease had greater WMF permeability compared to those with milder disease phenotype, but similar lesion permeability. Subjects receiving statin medications for routine cardiovascular indications had a trend of lower WMF, but not lesion, permeability. This is the first demonstration of brain vascular hyperpermeability in humans with an autosomal dominant disease, as predicted mechanistically. Brain permeability, more than lesion permeability, may serve as a biomarker of CCM disease activity, and help calibrate potential drug therapy.

  20. Clinical value of detection on serum monocyte chemotactant protein-1 and vascular endothelial cadherin levels in patients with acute cerebral infarction

    Institute of Scientific and Technical Information of China (English)

    Xia Zhou; Cheng Zhang

    2016-01-01

    Objective: To study the correlation of serum monocyte chemotactant protein-1 (MCP-1) and vascular endothelia cadherin (VE-cadherin) levels in patients with acute cerebral infarction, and nerve injury molecules, interleukins and matrix metalloproteinases. Methods: A total of 86 patients with acute cerebral infarction treated in our hospital from April 2012 to October 2015 were selected as the observation group and 50 healthy subjects in the same period treated in our hospital were selected as the control group. The serums were collected and the contents of MCP-1, VE-cadherin, heart-type fatty acid binding protein (H-FABP), S100 calcium binding protein B (S100B), neuron-specific enolase (NSE), interleukin-lb (IL-1b), IL-6, IL-17, IL-18, matrix metalloproteinase-2 (MMP2), MMP3 and MMP9 were measured. Results: The serum contents of MCP-1, VE-cadherin, H-FABP, S100B, NSE, IL-1b, IL-6, IL-17, IL-18, MMP2, MMP3 and MMP9 in observation group were significantly higher than those of control group. Carotid artery plaque formation and unstable plaque properties will increase the serum contents of MCP-1, VE-cadherin, H-FABP, S100B, NSE, IL-1b, IL-6, IL-17, IL-18, MMP2, MMP3 and MMP9 in patients with cerebral infarction. The serum levels of MCP-1, VE-cadherin and the contents of H-FABP, S100B, NSE, IL-1b, IL-6, IL-17, IL-18, MMP2, MMP3 and MMP9 were positively correlated. Conclusions: The serum levels of VE-cadherin and MCP-1 were significantly increased in patients with acute cerebral infarction. MCP-1 and VE-cadherin can increase the secretion of interleukins and matrix metalloproteinases, which can result in the carotid artery plaque formation, unstable plaque properties and the injury of nerve function.

  1. Clinical value of detection on ser um monocyte chemotactant protein-1 and vascular endothelial cadher in levels in patients with acute cerebral infarction

    Directory of Open Access Journals (Sweden)

    Xia Zhou

    2016-11-01

    Full Text Available Objective: To study the correlation of serum monocyte chemotactant protein-1 (MCP-1 and vascular endothelia cadherin (VE-cadherin levels in patients with acute cerebral infarction, and nerve injury molecules, interleukins and matrix metalloproteinases. Methods: A total of 86 patients with acute cerebral infarction treated in our hospital from April 2012 to October 2015 were selected as the observation group and 50 healthy subjects in the same period treated in our hospital were selected as the control group. The serums were collected and the contents of MCP-1, VE-cadherin, heart-type fatty acid binding protein (H-FABP, S100 calcium binding protein B (S100B, neuron-specific enolase (NSE, interleukin-lb (IL-1b, IL-6, IL-17, IL-18, matrix metalloproteinase-2 (MMP2, MMP3 and MMP9 were measured. Results: The serum contents of MCP-1, VE-cadherin, H-FABP, S100B, NSE, IL-1b, IL- 6, IL-17, IL-18, MMP2, MMP3 and MMP9 in observation group were significantly higher than those of control group. Carotid artery plaque formation and unstable plaque properties will increase the serum contents of MCP-1, VE-cadherin, H-FABP, S100B, NSE, IL-1b, IL-6, IL-17, IL-18, MMP2, MMP3 and MMP9 in patients with cerebral infarction. The serum levels of MCP-1, VE-cadherin and the contents of H-FABP, S100B, NSE, IL-1b, IL-6, IL-17, IL-18, MMP2, MMP3 and MMP9 were positively correlated. Conclusions: The serum levels of VE-cadherin and MCP-1 were significantly increased in patients with acute cerebral infarction. MCP-1 and VE-cadherin can increase the secretion of interleukins and matrix metalloproteinases, which can result in the carotid artery plaque formation, unstable plaque properties and the injury of nerve function.

  2. Vascular endothelial dysfunction and pharmacological treatment

    Institute of Scientific and Technical Information of China (English)

    Jin; Bo; Su

    2015-01-01

    The endothelium exerts multiple actions involving regulation of vascular permeability and tone, coagulation and fibrinolysis, inflammatory and immunological reactions and cell growth. Alterations of one or more such actions may cause vascular endothelial dysfunction. Different risk factors such as hypercholesterolemia, homocystinemia, hyperglycemia, hypertension, smo-king, inflammation, and aging contribute to the development of endothelial dysfunction. Mechanisms underlying endothelial dysfunction are multiple, including impaired endothelium-derived vasodilators, enhanced endothelium-derived vasoconstrictors, over production of reactive oxygen species and reactive nitrogen species, activation of inflammatory and immune reactions, and imbalance of coagulation and fibrinolysis. Endothelial dysfunction occurs in many cardiovascular diseases, which involves different mechanisms, depending on specific risk factors affecting the disease. Among these mechanisms, a reduction in nitric oxide(NO) bioavailability plays a central role in the development of endothelial dysfunction because NO exerts diverse physiological actions, including vasodilation, anti-inflammation, antiplatelet, antiproliferation and antimigration. Experimental and clinical studies have demonstrated that a variety of currently used or investigational drugs, such as angiotensin-converting enzyme inhibitors, angiotensin AT1 receptors blockers, angiotensin-(1-7), antioxidants, beta-blockers, calcium channel blockers, endothelial NO synthase enhancers, phosphodiesterase 5 inhibitors, sphingosine-1-phosphate and statins, exert endothelial protective effects. Due to the difference in mechanisms of action, these drugs need to be used according to specific mechanisms underlying endothelial dysfunction of the disease.

  3. Brain endothelial dysfunction in cerebral adrenoleukodystrophy.

    Science.gov (United States)

    Musolino, Patricia L; Gong, Yi; Snyder, Juliet M T; Jimenez, Sandra; Lok, Josephine; Lo, Eng H; Moser, Ann B; Grabowski, Eric F; Frosch, Matthew P; Eichler, Florian S

    2015-11-01

    See Aubourg (doi:10.1093/awv271) for a scientific commentary on this article.X-linked adrenoleukodystrophy is caused by mutations in the ABCD1 gene leading to accumulation of very long chain fatty acids. Its most severe neurological manifestation is cerebral adrenoleukodystrophy. Here we demonstrate that progressive inflammatory demyelination in cerebral adrenoleukodystrophy coincides with blood-brain barrier dysfunction, increased MMP9 expression, and changes in endothelial tight junction proteins as well as adhesion molecules. ABCD1, but not its closest homologue ABCD2, is highly expressed in human brain microvascular endothelial cells, far exceeding its expression in the systemic vasculature. Silencing of ABCD1 in human brain microvascular endothelial cells causes accumulation of very long chain fatty acids, but much later than the immediate upregulation of adhesion molecules and decrease in tight junction proteins. This results in greater adhesion and transmigration of monocytes across the endothelium. PCR-array screening of human brain microvascular endothelial cells after ABCD1 silencing revealed downregulation of both mRNA and protein levels of the transcription factor c-MYC (encoded by MYC). Interestingly, MYC silencing mimicked the effects of ABCD1 silencing on CLDN5 and ICAM1 without decreasing the levels of ABCD1 protein itself. Together, these data demonstrate that ABCD1 deficiency induces significant alterations in brain endothelium via c-MYC and may thereby contribute to the increased trafficking of leucocytes across the blood-brain barrier as seen in cerebral adrenouleukodystrophy.

  4. [The effects of microgravity on blood vessels and vascular endothelial cells].

    Science.gov (United States)

    Tang, Na-Ping; Li, Hua; Qiu, Yun-Liang; Zhou, Guo-Mina; Wang, Yan; Ma, Jing; Mei, Qi-Bing

    2014-10-01

    The dysfunction of vascular system is one of the main causes of orthostatic intolerance induced by microgravity. Vascular endothelial cell is a single layer on the inner wall of the blood vessel and is the important component of the blood vessel wall. Vascular endothelial cell plays a pivotal role in the regulation of vascular functions, such as serving as a permeability barrier, regulating vasoconstriction and vasodilatation. Recent studies have demonstrated that microgravity may have different effects on vascular sys- tem and vascular endothelial cells in different parts of the body, such as increasing vasoconstrictor reactivity and decreasing vasodilator reactivity of cerebral arteries, decreasing vasoconstrictor and vasodilator reactivity of carotid and abdominal aortic arteries, decreasing vasoconstrictor reactivity and increasing vasodilator reactivity of pulmonary arteries, decreasing vasoconstrictor reactivity of mesenteric arteries and veins and lower extremity arteries. In addition, microgravity can promote the growth of vascular endothelial cells in the large vessels and inhibit the growth of microvascular endothelial cells. This paper summarized the research progress in the effects of microgravity on blood vessels and vascular endothelial cells.

  5. Impact of Endothelial Microparticles on Coagulation, Inflammation, and Angiogenesis in Age-Related Vascular Diseases

    Directory of Open Access Journals (Sweden)

    Margaret Markiewicz

    2013-01-01

    Full Text Available Endothelial microparticles (EMPs are complex vesicular structures that originate from plasma membranes of activated or apoptotic endothelial cells. EMPs play a significant role in vascular function by altering the processes of inflammation, coagulation, and angiogenesis, and they are key players in the pathogenesis of several vascular diseases. Circulating EMPs are increased in many age-related vascular diseases such as coronary artery disease, peripheral vascular disease, cerebral ischemia, and congestive heart failure. Their elevation in plasma has been considered as both a biomarker and bioactive effector of vascular damage and a target for vascular diseases. This review focuses on the pleiotropic roles of EMPs and the mechanisms that trigger their formation, particularly the involvement of decreased estrogen levels, thrombin, and PAI-1 as major factors that induce EMPs in age-related vascular diseases.

  6. Cytoskeleton, cytoskeletal interactions, and vascular endothelial function

    Directory of Open Access Journals (Sweden)

    Wang J

    2012-12-01

    Full Text Available Jingli Wang,1 Michael E Widlansky1,21Department of Medicine, Cardiovascular Medicine Division, 2Department of Pharmacology, Medical College of Wisconsin, Milwaukee, Wisconsin, USAAbstract: Far from being inert, the vascular endothelium is a critical regulator of vascular function. While the endothelium participates in autocrine, paracrine, and endocrine signaling, it also transduces mechanical signals from the cell surface involving key cell structural elements. In this review, we discuss the structure of the vascular endothelium and its relationship to traditional cardiovascular risk factors and clinical cardiovascular events. Further, we review the emerging evidence that cell structural elements, including the glycocalyx, intercellular junctions, and cytoskeleton elements, help the endothelium to communicate with its environment to regulate vascular function, including vessel permeability and signal transduction via nitric oxide bioavailability. Further work is necessary to better delineate the regulatory relationships between known key regulators of vascular function and endothelial cell structural elements.Keywords: endothelium, shear stress, eNOS, cardiovascular risk factors, glycocalyx

  7. Insulin transcriptionally regulates argininosuccinate synthase to maintain vascular endothelial function

    OpenAIRE

    Haines, Ricci J.; Corbin, Karen D.; Pendleton, Laura C; Meininger, Cynthia J; Eichler, Duane C.

    2012-01-01

    Diminished vascular endothelial cell nitric oxide (NO) production is a major factor in the complex pathogenesis of diabetes mellitus. In this report, we demonstrate that insulin not only maintains endothelial NO production through regulation of endothelial nitric oxide synthase (eNOS), but also via the regulation of argininosuccinate synthase (AS), which is the rate-limiting step of the citrulline-NO cycle. Using serum starved, cultured vascular endothelial cells, we show that insulin up-regu...

  8. [Transcranial electrostimulation in chronic cerebral vascular insufficiency].

    Science.gov (United States)

    Voropaev, A A; Mochalov, A D

    2006-01-01

    The method of transcranial electrostimulation (TCES) has been used for treatment of 68 patients with chronic cerebral vascular insufficiency, stages I and II. A treatment course included 7 daily procedures. The influence of TCES was evaluated clinically, by EEG, transcranial ultrasonic Doppler study and hemodynamic indices in arteries and veins as well as by expression of trait and state anxiety. All the parameters were compared to those of the control group which was treated using conventional methods. TCES resulted in normalization of cerebral vascular reactivity, a decrease of venous circulation disturbances, positive influence on cerebral blood flow and EEG parameters, that corresponded to global improvement of the patients' state, regress of cephalgic syndrome and reduction of trait and state anxiety. The method is simple and safety and can be recommended for wide application including outpatient setting.

  9. Growth factor-and cytokine-stimulated endothelial progenitor cells in post-ischemic cerebral neovascularization

    Institute of Scientific and Technical Information of China (English)

    Philip V.Peplow

    2014-01-01

    Endothelial progenitor cells are resident in the bone marrow blood sinusoids and circulate in the peripheral circulation. They mobilize from the bone marrow after vascular injury and home to the site of injury where they differentiate into endothelial cells. Activation and mobilization of endothelial progenitor cells from the bone marrow is induced via the production and release of endothelial progenitor cell-activating factors and includes speciifc growth factors and cytokines in response to peripheral tissue hypoxia such as after acute ischemic stroke or trauma. Endotheli-al progenitor cells migrate and home to speciifc sites following ischemic stroke via growth factor/cytokine gradients. Some growth factors are less stable under acidic conditions of tissue isch-emia, and synthetic analogues that are stable at low pH may provide a more effective therapeutic approach for inducing endothelial progenitor cell mobilization and promoting cerebral neovas-cularization following ischemic stroke.

  10. Biophysical Cueing and Vascular Endothelial Cell Behavior

    Directory of Open Access Journals (Sweden)

    Joshua A. Wood

    2010-03-01

    Full Text Available Human vascular endothelial cells (VEC line the vessels of the body and are critical for the maintenance of vessel integrity and trafficking of biochemical cues. They are fundamental structural elements and are central to the signaling environment. Alterations in the normal functioning of the VEC population are associated with a number of vascular disorders among which are some of the leading causes of death in both the United States and abroad. VECs attach to their underlying stromal elements through a specialization of the extracellular matrix, the basement membrane. The basement membrane provides signaling cues to the VEC through its chemical constituents, by serving as a reservoir for cytoactive factors and through its intrinsic biophysical properties. This specialized matrix is composed of a topographically rich 3D felt-like network of fibers and pores on the nano (1–100 nm and submicron (100–1,000 nm size scale. The basement membrane provides biophysical cues to the overlying VECs through its intrinsic topography as well as through its local compliance (relative stiffness. These biophysical cues modulate VEC adhesion, migration, proliferation, differentiation, and the cytoskeletal signaling network of the individual cells. This review focuses on the impact of biophysical cues on VEC behaviors and demonstrates the need for their consideration in future vascular studies and the design of improved prosthetics.

  11. Acidente vascular cerebral e demência vascular no idoso

    OpenAIRE

    Ionel, Cristina

    2015-01-01

    Trabalho final de mestrado integrado em Medicina, apresentado à Faculdade de Medicina da Universidade de Coimbra. Em consequência de um fenómeno global de envelhecimento populacional, é expectável um aumento na prevalência de demência. A demência vascular é a segunda causa mais comum de demência, depois da doença de Alzheimer. Trata-se de uma entidade clínica bastante heterogénea, sendo o acidente vascular cerebral (AVC) um dos seus mecanismos subjacentes. No entanto, nem todos os doentes ...

  12. Expression of Interleukin-10 on Cerebral Vascular Endothelial Cells in Smoking Rats%烟草烟雾对大鼠脑血管内皮细胞白细胞介素10表达的影响

    Institute of Scientific and Technical Information of China (English)

    刘菲; 柳宗兰; 王一沙

    2011-01-01

    目的 观察不同吸烟量大鼠脑血管内皮细胞白细胞介素10的表达,探讨烟草烟雾导致脑缺血的发病机制.方法 健康Wistar大鼠60只,分为正常对照组、假暴露组、暴露卷烟烟气30天组、暴露卷烟烟气30天后停止暴露30天组(戒烟组)、暴露卷烟烟气90天高剂量组、暴露卷烟烟气90天低剂量组.通过免疫组织化学法观察大鼠脑血管内皮细胞白细胞介素10的表达.结果 正常对照组和假暴露组白细胞介素10的表达较多,暴露卷烟烟气90天高剂量组白细胞介素10的表达明显低于其他各被动吸烟组,戒烟组白细胞介素10的表达明显高于其他各被动吸烟组,各被动吸烟组白细胞介素10的表达较正常对照组和假暴露组减少(P<0.05).结论 烟草烟雾可致脑血管内皮细胞白细胞介素10的表达减少,可能在缺血性脑血管病的发病中起重要作用.%Aim To observe the expression of interleukin-10 (IL-10) on cerebral vascular endothelial cells in smoking rats, and to discuss the mechanism of ischemia in brain caused by smoking. Methods 60 health Wistar rats were divied into 6 groups: normal control group, sham exposure group, exposed cigarette smoke 30 days group, exposed cigarette smoke 30 days then stopping exposion for 30 days group, exposed cigarette smoke 90 days high dose group and exposed cigarette smoke 90 days low dose group. The expression of IL-10 were observed in smoking rats by immunohistochemistry stain. Results The expression of IL-10 in normal control group and sham exposure group were more. The expression of IL-10 in exposed cigarette smoke 90 days high dose group were significantly lower than those in the other passive smoking groups. The expression of IL-10 in exposed cigarette smoke 30 days then stopping exposure for 30 days group were significantly higher than those in the other passive smoking groups. The expression of IL-10 in the passive smoking groups were significantly lower than

  13. Associations among cerebral microbleeds, cerebral large-artery diseases and endothelial function.

    Science.gov (United States)

    Peng, Qing; Huang, Yining; Sun, Wei; Xing, Haiying

    2014-01-01

    Endothelial dysfunction is not only an early stage of atherosclerosis, but also involved in the pathogenesis of cerebral small-vessel diseases. Patients with cerebral microbleeds (CMBs) may have arteriolosclerosis as well as systemic atherosclerosis. However, little is known about the associations among CMBs, atherosclerosis of cerebral large arteries, and endothelial function. Our study aimed to investigate the relationships among them. This was a cross-sectional study. Ninety patients hospitalized in Peking University First Hospital with acute ischemic stroke were enrolled consecutively between November 1, 2007 and January 31, 2008. All subjects underwent transcranial Doppler and carotid color duplex ultrasonography to record the intima-media thickness (IMT) of common carotid artery, carotid plaque, and cerebral artery stenosis. Brain magnetic resonance imaging (MRI) routine sequences and gradient recall-echo T2(*)-weighted imaging were performed to count CMBs with clinical data blindness. Endothelial function was evaluated using flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD) of the brachial artery. FMD and NMD were examined by an experienced vascular sonographer using a high-resolution ultrasound. Thirty cases (33.3%) had CMBs with counts ranging from 1 to 30. Both FMD ((9.9 ± 4.8)% vs. (15. 2 ± 7.4)%, P = 0.001) and NMD ((13.7 ± 6.1)% vs. (19.0 ± 7.4)%, P = 0.001) were significantly decreased in CMB-positive patients than in CMB-negative patients. No significant relationships were demonstrated between CMBs and intracranial and/or extracranial artery stenosis. The frequencies of CMBs in patients with IMT≥1.0 mm, carotid plaque, and extracranial artery stenosis were 37.5%, 39.4%, and 47.6% respectively, with no significant difference, but much higher than in patients with IMT CMBs, as well as previous ischemic stroke. In contrast, NMD was not correlated with CMBs. CMBs may coexist with cerebral atherosclerosis in ischemic stroke

  14. MMP-2 Is Mainly Expressed in Arterioles and Contributes to Cerebral Vascular Remodeling Associated with TGF-β1 Signaling.

    Science.gov (United States)

    Hua, Ye; Zhang, Weifeng; Xie, Zhenying; Xu, Nanfei; Lu, Yunnan

    2016-07-01

    There is increasing evidence to suggest that matrix metalloproteinases (MMPs) play a crucial role in vascular remodeling. It has been reported that hypoxia stimulated MMP-9 expression in brain endothelial cells and MMP-9 plays an important role in cerebral vascular remodeling. However, little is known about MMP-2 in the cerebral vessels remodeling. Herein, the aim of this study is to examine the class of vessel and cell type expressing MMP-2 in cerebral vessels and to investigate its potential role in vascular remodeling. In the present study, dual-immunofluorescence assay showed that MMP-2 was mainly expressed in arterioles. In addition, we found that MMP-2 expression in cerebral vessels was derived from endothelial cells, not astrocyte cells. Notably, in the normoxic central nervous system (CNS), there was no effect on vascular development, integrity, or endothelial proliferation when MMP-2 was knocked out, but lack of MMP-2 led to defective arteriolar remodeling and associated with transforming growth factor β1 (TGF-β1) signaling in CNS. Moreover, blocking TGF-β with SB431542, a specific TGF-β inhibitor, significantly reduced the messenger RNA (mRNA) and protein expression levels of MMP-2 in human umbilical vein endothelial cells (HUVECs). Our findings reveal that the level of MMP-2 is high in arteriolar endothelial cells and demonstrate a novel connection between MMP-2 and TGF-β1 signaling in cerebral vascular remodeling.

  15. Pathogenesis of diabetic cerebral vascular diseasecomplication

    Institute of Scientific and Technical Information of China (English)

    Ren-Shi Xu

    2015-01-01

    Diabetes mellitus is one of the most potent independentrisk factors for the development of diabetic cerebralvascular disease (CVD). Many evidences suggested thathyperglycemia caused excess free fatty acids, the lossof endothelium-derived nitric oxide, insulin resistance,the prothrombotic state, endothelial dysfunction,the abnormal release of endothelial vasoactivators,vascular smooth muscle dysfunction, oxidative stress,and the downregulation of miRs participated in vesselgeneration and recovery as well as the balance ofendotheliocytes. In turn, these abnormalities, mainly viaphosphatidylinositol 3 kinase, mitogen-activated proteinkinase, polyol, hexosamine, protein kinase C activation,and increased generation of advanced glycosylation endproducts pathway, play an important role in inducingdiabetic CVD complication. A deeper comprehensionof pathogenesis producing diabetic CVD could offerbase for developing new therapeutic ways preventingdiabetic CVD complications, therefore, in the paper wemainly reviewed present information about the possiblepathogenesis of diabetic CVD complication.

  16. The effect of vascular endothelial growth factor-1 expression on ...

    African Journals Online (AJOL)

    Riyad Bendardaf

    2017-02-28

    Feb 28, 2017 ... The effect of vascular endothelial growth factor-1 expression on survival of ... Sharjah, Sharjah, United Arab Emirates; cFaculty of Medicine, Suez Canal University, ..... levels were significantly higher in patients who sub-.

  17. Advances in the Management of Cerebral Vascular Disease

    Directory of Open Access Journals (Sweden)

    Muhammad Imran Qadir

    2015-06-01

    Full Text Available A cerebral vascular disease occurred with the arteries of brain due to the less supply of blood.  Stroke is mostly caused by cerebral vascular disease and it is also a common cause of vascular dementia due to reduced oxygen supply and blood flow to the brain. In industrialized countries, neurologic disability is most frequently caused by cerebeovascular disease. Individuals with cardiovascular disease, diabetes and high blood pressure etc are at higher possibility for cerebral vascular disease. After malignancy and heart disease, cerebral vascular disease is the third leading of death and estimated that an average 500,000 new stroke occurred in each year. Advance techniques such as Carotid Endarterectomy, Magnetic resonance imaging, Angiography and Single photon emission computed tomography etc are used for management of cerebral vascular disease.

  18. Glutathione in Cerebral Microvascular Endothelial Biology and Pathobiology: Implications for Brain Homeostasis

    Directory of Open Access Journals (Sweden)

    Wei Li

    2012-01-01

    Full Text Available The integrity of the vascular endothelium of the blood-brain barrier (BBB is central to cerebrovascular homeostasis. Given the function of the BBB as a physical and metabolic barrier that buffers the systemic environment, oxidative damage to the endothelial monolayer will have significant deleterious impact on the metabolic, immunological, and neurological functions of the brain. Glutathione (GSH is a ubiquitous major thiol within mammalian cells that plays important roles in antioxidant defense, oxidation-reduction reactions in metabolic pathways, and redox signaling. The existence of distinct GSH pools within the subcellular organelles supports an elegant mode for independent redox regulation of metabolic processes, including those that control cell fate. GSH-dependent homeostatic control of neurovascular function is relatively unexplored. Significantly, GSH regulation of two aspects of endothelial function is paramount to barrier preservation, namely, GSH protection against oxidative endothelial cell injury and GSH control of postdamage cell proliferation in endothelial repair and/or wound healing. This paper highlights our current insights and hypotheses into the role of GSH in cerebral microvascular biology and pathobiology with special focus on endothelial GSH and vascular integrity, oxidative disruption of endothelial barrier function, GSH regulation of endothelial cell proliferation, and the pathological implications of GSH disruption in oxidative stress-associated neurovascular disorders, such as diabetes and stroke.

  19. Insulin transcriptionally regulates argininosuccinate synthase to maintain vascular endothelial function.

    Science.gov (United States)

    Haines, Ricci J; Corbin, Karen D; Pendleton, Laura C; Meininger, Cynthia J; Eichler, Duane C

    2012-04-27

    Diminished vascular endothelial cell nitric oxide (NO) production is a major factor in the complex pathogenesis of diabetes mellitus. In this report, we demonstrate that insulin not only maintains endothelial NO production through regulation of endothelial nitric oxide synthase (eNOS), but also via the regulation of argininosuccinate synthase (AS), which is the rate-limiting step of the citrulline-NO cycle. Using serum starved, cultured vascular endothelial cells, we show that insulin up-regulates AS and eNOS transcription to support NO production. Moreover, we show that insulin enhances NO production in response to physiological cues such as bradykinin. To translate these results to an in vivo model, we show that AS transcription is diminished in coronary endothelial cells isolated from rats with streptozotocin (STZ)-induced diabetes. Importantly, we demonstrate restoration of AS and eNOS transcription by insulin treatment in STZ-diabetic rats, and show that this restoration was accompanied by improved endothelial function as measured by endothelium-dependent vasorelaxation. Overall, this report demonstrates, both in cell culture and whole animal studies, that insulin maintains vascular function, in part, through the maintenance of AS transcription, thus ensuring an adequate supply of arginine to maintain vascular endothelial response to physiological cues. Copyright © 2012 Elsevier Inc. All rights reserved.

  20. l-arginine and l-NMMA for assessing cerebral endothelial dysfunction in ischaemic cerebrovascular disease

    DEFF Research Database (Denmark)

    Karlsson, William K; Sørensen, Caspar G; Kruuse, Christina

    2017-01-01

    Endothelial dysfunction (ED), in particular cerebral ED, may be an essential biomarker for ischaemic cerebrovascular disease. However, there is no consensus on methods to best estimate cerebral ED. In this systematic review, we evaluate the use of l-arginine and NG -monomethyl-l-arginine (l......-NMMA) for assessment of cerebral ED. A systematic search of PubMed, EMBASE and the Cochrane Library was done. We included studies investigating cerebrovascular response to l-arginine or l-NMMA in human subjects with vascular risk factors or ischaemic cerebrovascular disease. Seven studies (315 subjects) were eligible...... according to inclusion and exclusion criteria. Studies investigated the effect of age (n=2), type 2 diabetes mellitus (DM) (n=1), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (n=1), leukoaraiosis (n=1), and prior ischaemic stroke or transient ischaemic...

  1. Endothelial Repair in Childhood Arterial Ischaemic Stroke with Cerebral Arteriopathy

    Directory of Open Access Journals (Sweden)

    Despina Eleftheriou

    2015-06-01

    Full Text Available Background: We have previously shown that recurrent arterial ischaemic stroke (AIS in children with cerebral arteriopathy is associated with increased circulating endothelial cells and endothelial microparticles, consistent with ongoing endothelial injury. To date, however, little is known about endothelial repair responses in childhood AIS. We examined the relationship between the number and function of circulating endothelial progenitor cells (EPC, the levels of brain-derived neurotrophic factor (BDNF and AIS recurrence. Methods: Flow cytometry was used to identify peripheral blood mononuclear cells positive for CD34/kinase insert domain-containing receptor (KDR. In a subgroup of patients (5 in each group selected at random, monocytic EPC function was assessed by colony-forming unit (EPC-CFU capacity and incorporation into endothelial cell networks in Matrigel. BDNF was measured using ELISA. Results: Thirty-five children, aged 12 years (range: 5-16.5; 9 males, with AIS and cerebral arteriopathy were studied; 10 had recurrent AIS. CD34+/KDR+ cells were significantly higher in recurrent AIS compared to non-recurrent AIS patients (p = 0.005 and controls (p = 0.0002. EPC-CFU and EPC incorporation into endothelial cell networks were significantly reduced in recurrent compared to non-recurrent AIS patients (p = 0.04 and p = 0.01, respectively. Levels of BDNF were significantly higher in recurrent compared to non-recurrent AIS patients (p = 0.0008 and controls (p = 0.0002. Conclusions: Children with recurrent AIS and cerebral arteriopathy had increased circulating CD34+/KDR+ cells and BDNF consistent with an endothelial repair response. However, EPC function was impaired. Future studies are needed to examine whether suboptimal endothelial repair contributes to childhood AIS recurrence.

  2. Cerebral cavernous malformations proteins inhibit Rho kinase to stabilize vascular integrity.

    Science.gov (United States)

    Stockton, Rebecca A; Shenkar, Robert; Awad, Issam A; Ginsberg, Mark H

    2010-04-12

    Endothelial cell-cell junctions regulate vascular permeability, vasculogenesis, and angiogenesis. Familial cerebral cavernous malformations (CCMs) in humans result from mutations of CCM2 (malcavernin, OSM, MGC4607), PDCD10 (CCM3), or KRIT1 (CCM1), a Rap1 effector which stabilizes endothelial cell-cell junctions. Homozygous loss of KRIT1 or CCM2 produces lethal vascular phenotypes in mice and zebrafish. We report that the physical interaction of KRIT1 and CCM2 proteins is required for endothelial cell-cell junctional localization, and lack of either protein destabilizes barrier function by sustaining activity of RhoA and its effector Rho kinase (ROCK). Protein haploinsufficient Krit1(+/-) or Ccm2(+/-) mouse endothelial cells manifested increased monolayer permeability in vitro, and both Krit1(+/-) and Ccm2(+/-) mice exhibited increased vascular leak in vivo, reversible by fasudil, a ROCK inhibitor. Furthermore, we show that ROCK hyperactivity occurs in sporadic and familial human CCM endothelium as judged by increased phosphorylation of myosin light chain. These data establish that KRIT1-CCM2 interaction regulates vascular barrier function by suppressing Rho/ROCK signaling and that this pathway is dysregulated in human CCM endothelium, and they suggest that fasudil could ameliorate both CCM disease and vascular leak.

  3. Loss of the endothelial glycocalyx links albuminuria and vascular dysfunction.

    Science.gov (United States)

    Salmon, Andrew H J; Ferguson, Joanne K; Burford, James L; Gevorgyan, Haykanush; Nakano, Daisuke; Harper, Steven J; Bates, David O; Peti-Peterdi, Janos

    2012-08-01

    Patients with albuminuria and CKD frequently have vascular dysfunction but the underlying mechanisms remain unclear. Because the endothelial surface layer, a meshwork of surface-bound and loosely adherent glycosaminoglycans and proteoglycans, modulates vascular function, its loss could contribute to both renal and systemic vascular dysfunction in proteinuric CKD. Using Munich-Wistar-Fromter (MWF) rats as a model of spontaneous albuminuric CKD, multiphoton fluorescence imaging and single-vessel physiology measurements revealed that old MWF rats exhibited widespread loss of the endothelial surface layer in parallel with defects in microvascular permeability to both water and albumin, in both continuous mesenteric microvessels and fenestrated glomerular microvessels. In contrast to young MWF rats, enzymatic disruption of the endothelial surface layer in old MWF rats resulted in neither additional loss of the layer nor additional changes in permeability. Intravenous injection of wheat germ agglutinin lectin and its adsorption onto the endothelial surface layer significantly improved glomerular albumin permeability. Taken together, these results suggest that widespread loss of the endothelial surface layer links albuminuric kidney disease with systemic vascular dysfunction, providing a potential therapeutic target for proteinuric kidney disease.

  4. Synergism of matrix stiffness and vascular endothelial growth factor on mesenchymal stem cells for vascular endothelial regeneration.

    Science.gov (United States)

    Wingate, Kathryn; Floren, Michael; Tan, Yan; Tseng, Pi Ou Nancy; Tan, Wei

    2014-09-01

    Mesenchymal stem cells (MSCs) hold tremendous potential for vascular tissue regeneration. Research has demonstrated that individual factors in the cell microenvironment such as matrix elasticity and growth factors regulate MSC differentiation to vascular lineage. However, it is not well understood how matrix elasticity and growth factors combine to direct the MSC fate. This study examines the combined effects of matrix elasticity and vascular endothelial growth factor (VEGF) on both MSC differentiation into endothelial lineage and MSC paracrine signaling. MSCs were seeded in soft nanofibrous matrices with or without VEGF, and in Petri dishes with or without VEGF. Only MSCs seeded in three-dimensional soft matrices with VEGF showed significant increases in the expression of endothelial markers (vWF, eNOS, Flt-1, and Flk-1), while eliminating the expression of smooth muscle marker (SM-α-actin). MSCs cultured in VEGF alone on two-dimensional dishes showed increased expression of both early-stage endothelial and smooth muscle markers, indicating immature vascular differentiation. Furthermore, MSCs cultured in soft matrices with VEGF showed faster upregulation of endothelial markers compared with MSCs cultured in VEGF alone. Paracrine signaling studies found that endothelial cells cultured in the conditioned media from MSCs differentiated in the soft matrix and VEGF condition exhibited increased migration and formation of capillary-like structures. These results demonstrate that VEGF and soft matrix elasticity act synergistically to guide MSC differentiation into mature endothelial phenotype while enhancing paracrine signaling. Therefore, it is critical to control both mechanical and biochemical factors to safely regenerate vascular tissues with MSCs.

  5. The effect of ASK1 on vascular permeability and edema formation in cerebral ischemia.

    Science.gov (United States)

    Song, Juhyun; Cheon, So Yeong; Lee, Won Taek; Park, Kyung Ah; Lee, Jong Eun

    2015-01-21

    Apoptosis signal-regulating kinase-1 (ASK1) is the mitogen-activated protein kinase kinase kinase (MAPKKK) and participates in the various central nervous system (CNS) signaling pathways. In cerebral ischemia, vascular permeability in the brain is an important issue because regulation failure of it results in edema formation and blood-brain barrier (BBB) disruption. To determine the role of ASK1 on vascular permeability and edema formation following cerebral ischemia, we first investigated ASK1-related gene expression using microarray analyses of ischemic brain tissue. We then measured protein levels of ASK1 and vascular endothelial growth factor (VEGF) in brain endothelial cells after hypoxia injury. We also examined protein expression of ASK1 and VEGF, edema formation, and morphological alteration through cresyl violet staining in ischemic brain tissue using ASK1-small interference RNA (ASK1-siRNA). Finally, immunohistochemistry was performed to examine VEGF and aquaporin-1 (AQP-1) expression in ischemic brain injury. Based on our findings, we propose that ASK1 is a regulating factor of vascular permeability and edema formation in cerebral ischemia.

  6. Decreased expression of serum and microvascular vascular endothelial growth factor receptor-2 in meningococcal sepsis*.

    NARCIS (Netherlands)

    Flier, M. van der; Baerveldt, E.M.; Miedema, A.; Hartwig, N.G.; Hazelzet, J.A.; Emonts, M.; Groot, R. de; Prens, E.P.; Vught, A.J. van; Jansen, N.J.

    2013-01-01

    OBJECTIVES: To determine the skin microvessel expression of vascular endothelial growth factor receptor 2 and serum-soluble vascular endothelial growth factor receptor 2 levels in children with meningococcal sepsis. DESIGN: Observational study. SETTING: Two tertiary academic children hospital PICUs.

  7. Vascular endothelial growth factor a in eyes with uveal melanoma.

    NARCIS (Netherlands)

    Missotten, G.S.; Notting, I.C.; Schlingemann, R.O.; Zijlmans, H.J.; Lau, C.; Eilers, P.H.; Keunen, J.E.E.; Jager, M.J.

    2006-01-01

    OBJECTIVES: To determine the presence of vascular endothelial growth factor A (VEGF-A) in the aqueous humor of eyes with uveal melanoma and to identify its source. METHODS: The VEGF-A concentrations were determined in aqueous humor samples obtained after enucleation from 74 eyes with untreated uveal

  8. Vascular Endothelial Growth Factor, diagnostic and therapeutic aspects

    NARCIS (Netherlands)

    Kusumanto, Yoka Hadiani

    2006-01-01

    This thesis focuses on the diagnostic and therapeutic potential of Vascular Endothelial Growth Factor, an angiogenic growth factor. Since the recognition of VEGF’s pivotal role in physiological and pathological angiogenesis research has evolved from cell culture and animal experiments to application

  9. Circulating vascular endothelial growth factor during the normal menstrual cycle

    NARCIS (Netherlands)

    Kusumanto, YH; Hospers, GAP; Sluiter, WJ; Dam, WA; Meijer, C; Mulder, NH

    2004-01-01

    Background: The purpose of the study was to investigate whether cycle-related variations in circulating Vascular Endothelial Growth Factor (VEGF) levels would increase the metastatic potential at specific times during the menstrual cycle. Materials and Methods: VEGF levels in serum and whole blood

  10. Circulating vascular endothelial growth factor during the normal menstrual cycle

    NARCIS (Netherlands)

    Kusumanto, YH; Hospers, GAP; Sluiter, WJ; Dam, WA; Meijer, C; Mulder, NH

    2004-01-01

    Background: The purpose of the study was to investigate whether cycle-related variations in circulating Vascular Endothelial Growth Factor (VEGF) levels would increase the metastatic potential at specific times during the menstrual cycle. Materials and Methods: VEGF levels in serum and whole blood w

  11. Functional genomics of vascular endothelial cells

    OpenAIRE

    Wallgard, Elisabet

    2008-01-01

    Angiogenesis, the formation of new blood vessels from preexisting ones, is a process involved in normal development as well as in several pathological conditions, such as cancer, ischemic heart disease, wound healing and certain retinal complications. Antiangiogenic targeting is therefore a promising new therapeutic principle. However, few blood vessel-specific drug targets have been identified, and information is still limited about endothelial cell (EC)-specific molecular ...

  12. Oxidative stress affects processing of amyloid precursor protein in vascular endothelial cells.

    Science.gov (United States)

    Muche, Abebe; Arendt, Thomas; Schliebs, Reinhard

    2017-01-01

    Oxidative stress is thought to be a key player in the pathogenesis of neurodegenerative dementia, including Alzheimer's disease (AD). It has been assumed that oxidative stress contributes to the ß-amyloid deposition in cerebral blood vessels. In order to prove this hypothesis, we examined the effect of oxidative stress on the processing of amyloid precursor protein (APP) in primary endothelial cells (EC) derived from cerebral cortical tissue of transgenic Tg2576 mice. Following exposure of EC by 1 μM hydrogen peroxide for up to 48 hours, formation and secretion of APP cleavage products sAPPα and sAPPß into the culture medium as well as the expression of endothelial APP were assessed. Oxidative stress resulted in enhanced secretion of sAPPß into the culture medium as compared to controls (absence of hydrogen peroxide), which was accompanied by an increased APP expression, induction of VEGF synthesis, nitric oxide and oxygen free radicals productions, and differential changes of endothelial phospo-p42/44 MAPK expression. The data suggest that oxidative stress may represent a major risk factor in causing Aß deposition in the brain vascular system by initiating the amyloidogenic route of endothelial APP processing. The enhanced β-secretase activity following oxidative stress exposure, possibly promoted by phosphorylation of p42/44 MAPK.

  13. Curcumin and folic acid abrogated methotrexate induced vascular endothelial dysfunction.

    Science.gov (United States)

    Sankrityayan, Himanshu; Majumdar, Anuradha S

    2016-01-01

    Methotrexate, an antifolate drug widely used in rheumatoid arthritis, psoriasis, and cancer, is known to cause vascular endothelial dysfunction by causing hyperhomocysteinemia, direct injury to endothelium or by increasing the oxidative stress (raising levels of 7,8-dihydrobiopterin). Curcumin is a naturally occurring polyphenol with strong antioxidant and anti-inflammatory action and therapeutic spectra similar to that of methotrexate. This study was performed to evaluate the effects of curcumin on methotrexate induced vascular endothelial dysfunction and also compare its effect with that produced by folic acid (0.072 μg·g(-1)·day(-1), p.o., 2 weeks) per se and in combination. Male Wistar rats were exposed to methotrexate (0.35 mg·kg(-1)·day(-1), i.p.) for 2 weeks to induce endothelial dysfunction. Methotrexate exposure led to shedding of endothelium, decreased vascular reactivity, increased oxidative stress, decreased serum nitrite levels, and increase in aortic collagen deposition. Curcumin (200 mg·kg(-1)·day(-1) and 400 mg·kg(-1)·day(-1), p.o.) for 4 weeks prevented the increase in oxidative stress, decrease in serum nitrite, aortic collagen deposition, and also vascular reactivity. The effects were comparable with those produced by folic acid therapy. The study shows that curcumin, when concomitantly administered with methotrexate, abrogated its vascular side effects by preventing an increase in oxidative stress and abating any reduction in physiological nitric oxide levels.

  14. Effects of ginsenosides on vascular reactivity in rat cerebral and renal arteries

    Institute of Scientific and Technical Information of China (English)

    WONG Wing-tak; LEUNG Fung-ping; YUNG Lai-hang; TIAN Xiao-yu; WONG Ricky Ngok Shun; HUANG Yu

    2008-01-01

    Objective To investigate possible mechanisms underlying the antioxidant property (1) and the in vitro vasodilator effects (2) of the two ginsenosides, Rb1 and Rg1, in isolated rat renal and cerebral arteries. Methods Arterial rings were mounted in a multi-channel myograph for recording of isometric tension. To examine the antioxidant activity, some rings were exposed to a free radical-generating reaction (hypoxan-thine and xanthine oxidase) with and without pre-treatment with ginsenosides. The calcium antagonistic effects were tested on rings contracted by membrane depolarization in elevated extracellular potassium ions, a condition that promoted Ca2+ influx in vascular smooth muscle cells. Results Ginsenosides protected endothelial function (endothelial nitric oxide-dependent relaxation) against oxidative stress; (2) ginsenoside Rb1 reduced the high K+ -induced contractions of both renal and cerebral arteries while ginsenoside Rgl relaxed the rat cerebral artery but not the renal artery. Conclusions Ginsenosides are vaso-protective via (1) the antioxidant activity which protects endothelial cell function and (2) the inhibition of Ca2+ influx through voltage-sensitive Ca2+ channels in vascular smooth muscle. The vasodilator effects may suggest the potential preventive or therapeutic values of ginsenosides against stroke and renal hypertension.

  15. An in vitro method for evaluating vascular endothelial ADPase activity.

    Science.gov (United States)

    Caprino, L; Togna, A R; Stella, C; Togna, G

    1996-06-01

    Some xenobiotics, known to promote the development of thrombotic phenomena, affect vascular endothelium ADPase, a regulatory enzyme that inactivates vaso- and platelet-active adenine nucleotides. This proposed new experimental approach represents an improved method of evaluation of vascular endothelial ADPase activity which is assessed by measuring, at pre-established times, the degradation rate of exogenous ADP incubated with aortic bovine patches. The ADP dosage was performed by using a spectrophotometric enzymatic assay. Statistical analyses showed that the method is capable of highlighting the linearity of the ADPase activity time-course, thus indicating that the slopes of time-degradation curves of ADP are a valid index for this endothelial ectoenzyme activity. Results obtained with ADPase inhibiting or stimulating agent confirm that this in vitro method is an efficient tool for estimating the ability of xenobiotics or drugs to modify the nonthrombogenic properties of vascular endothelium.

  16. Neuropilin-1 modulates vascular endothelial growth factor-induced poly(ADP-ribose)-polymerase leading to reduced cerebrovascular apoptosis.

    Science.gov (United States)

    Mey, Lilli; Hörmann, Mareike; Schleicher, Nadine; Reuter, Peter; Dönges, Simone; Kinscherf, Ralf; Gassmann, Max; Gerriets, Tibo; Al-Fakhri, Nadia

    2013-11-01

    Cerebral ischemia is encompassed by cerebrovascular apoptosis, yet the mechanisms behind apoptosis regulation are not fully understood. We previously demonstrated inhibition of endothelial apoptosis by vascular endothelial growth factor (VEGF) through upregulation of poly(ADP-ribose)-polymerase (PARP) expression. However, PARP overactivation through oxidative stress can lead to necrosis. This study tested the hypothesis that neuropilin-1 (NP-1), an alternative VEGF receptor, regulates the response to cerebral ischemia by modulating PARP expression and, in turn, apoptosis inhibition by VEGF. In endothelial cell culture, NP-1 colocalized with VEGF receptor-2 (VEGFR-2) and acted as its coreceptor. This significantly enhanced VEGF-induced PARP mRNA and protein expression demonstrated by receptor-specific inhibitors and VEGF-A isoforms. NP-1 augmented the inhibitory effect of VEGF/VEGFR-2 interaction on apoptosis induced by adhesion inhibition through the αV-integrin inhibitor cRGDfV. NP-1/VEGFR-2 signal transduction involved JNK and Akt. In rat models of permanent and temporary middle cerebral artery occlusion, the ischemic cerebral hemispheres displayed endothelial and neuronal apoptosis next to increased endothelial NP-1 and VEGFR-2 expression compared to non-ischemic cerebral hemispheres, sham-operated or untreated controls. Increased vascular superoxide dismutase-1 and catalase expression as well as decreased glycogen reserves indicated oxidative stress in the ischemic brain. Of note, protein levels of intact PARP remained stable despite pro-apoptotic conditions through increased PARP mRNA production during cerebral ischemia. In conclusion, NP-1 is upregulated in conditions of imminent cerebrovascular apoptosis to reinforce apoptosis inhibition and modulate VEGF-dependent PARP expression and activation. We propose that NP-1 is a key modulator of VEGF maintaining cerebrovascular integrity during ischemia. Modulating the function of NP-1 to target PARP could help to

  17. Vascular endothelial cells and dysfunctions: role of melatonin.

    Science.gov (United States)

    Rodella, Luigi Fabrizio; Favero, Gaia; Foglio, Eleonora; Rossini, Claudia; Castrezzati, Stefania; Lonati, Claudio; Rezzani, Rita

    2013-01-01

    Several pathological conditions, including hypertension, atherosclerosis, diabetes, ischemia/reperfusion injury and nicotine-induced vasculopathy, are associated with vascular endothelial dysfunction characterized by altered secretory output of endothelial cells. Therefore there is a search for molecules and interventions that could restore endothelial function, in particular augmenting NO production, reducing the generation of free radicals and vasoconstrictors and preventing undesired inflammation. The pineal hormone melatonin exhibits several endothelium protective properties: it scavenges free radicals, activates antioxidant defence enzymes, normalizes lipid and blood pressure profile and increases NO bioavailability. Melatonin improved vascular function in experimental hypertension, reducing intimal infiltration and restoring NO production. Melatonin improved the NO pathway also in animal models for the study of diabetes and prevented NO down-regulation and adhesive molecules up-regulation in nicotine-induced vasculopathy. The protection against endothelial damage, vasoconstriction, platelet aggregation and leukocyte infiltration might contribute to the beneficial effects against ischemia-reperfusion injury by melatonin. Therefore, melatonin administration has endothelium-protective potential in several pathological conditions. Nevertheless, it still needs to be established, whether melatonin is able to revert already established endothelial dysfunction in these conditions.

  18. Stabiliztin of VEGFR2 Signaling by Cerebral Cavernous Malformation 3 is Critical for Vascular Development

    Energy Technology Data Exchange (ETDEWEB)

    Y He; H Zhang; L Yu; M Gunel; T Boggon; H Chen; W Min

    2011-12-31

    Cerebral cavernous malformations (CCMs) are human vascular malformations caused by mutations in three genes of unknown function: CCM1, CCM2, and CCM3. CCM3, also known as PDCD10 (programmed cell death 10), was initially identified as a messenger RNA whose abundance was induced by apoptotic stimuli in vitro. However, the in vivo function of CCM3 has not been determined. Here, we describe mice with a deletion of the CCM3 gene either ubiquitously or specifically in the vascular endothelium, smooth muscle cells, or neurons. Mice with global or endothelial cell-specific deletion of CCM3 exhibited defects in embryonic angiogenesis and died at an early embryonic stage. CCM3 deletion reduced vascular endothelial growth factor receptor 2 (VEGFR2) signaling in embryos and endothelial cells. In response to VEGF stimulation, CCM3 was recruited to and stabilized VEGFR2, and the carboxyl-terminal domain of CCM3 was required for the stabilization of VEGFR2. Indeed, the CCM3 mutants found in human patients lacking the carboxyl-terminal domain were labile and were unable to stabilize and activate VEGFR2. These results demonstrate that CCM3 promotes VEGFR2 signaling during vascular development.

  19. Characterization of vascular endothelial progenitor cells from chicken bone marrow

    Directory of Open Access Journals (Sweden)

    Bai Chunyu

    2012-05-01

    Full Text Available Abstract Background Endothelial progenitor cells (EPC are a type of stem cell used in the treatment of atherosclerosis, vascular injury and regeneration. At present, most of the EPCs studied are from human and mouse, whereas the study of poultry-derived EPCs has rarely been reported. In the present study, chicken bone marrow-derived EPCs were isolated and studied at the cellular level using immunofluorescence and RT-PCR. Results We found that the majority of chicken EPCs were spindle shaped. The growth-curves of chicken EPCs at passages (P 1, -5 and -9 were typically “S”-shaped. The viability of chicken EPCs, before and after cryopreservation was 92.2% and 81.1%, respectively. Thus, cryopreservation had no obvious effects on the viability of chicken EPCs. Dil-ac-LDL and FITC-UAE-1 uptake assays and immunofluorescent detection of the cell surface markers CD34, CD133, VEGFR-2 confirmed that the cells obtained in vitro were EPCs. Observation of endothelial-specific Weibel-Palade bodies using transmission electron microscopy further confirmed that the cells were of endothelial lineage. In addition, chicken EPCs differentiated into endothelial cells and smooth muscle cells upon induction with VEGF and PDGF-BB, respectively, suggesting that the chicken EPCs retained multipotency in vitro. Conclusions These results suggest that chicken EPCs not only have strong self-renewal capacity, but also the potential to differentiate into endothelial and smooth muscle cells. This research provides theoretical basis and experimental evidence for potential therapeutic application of endothelial progenitor cells in the treatment of atherosclerosis, vascular injury and diabetic complications.

  20. Vascular endothelial dysfunction: a tug of war in diabetic nephropathy?

    Science.gov (United States)

    Balakumar, Pitchai; Chakkarwar, Vishal Arvind; Krishan, Pawan; Singh, Manjeet

    2009-03-01

    Vascular endothelium regulates vascular tone and maintains free flow of blood in vessels. Vascular endothelial dysfunction (VED) results in reduced activation of endothelial nitric oxide synthase (eNOS), reduced generation and bioavailability of nitric oxide (NO) and increased production of reactive oxygen species (ROS). The eNOS uncoupling in VED leads to eNOS mediated production of ROS that further damage the endothelial cells by upregulating the proinflammatory mediators and adhesion molecules. VED has been associated in the pathogenesis of hypertension, atherosclerosis, coronary artery diseases, diabetes mellitus and nephropathy. Diabetes is a chronic metabolic disorder characterized by hyperglycemia followed by micro and macrovascular complications. A correlation between diabetes and VED has been demonstrated in various studies. The downregulation of eNOS in diabetes has been noted to accelerate diabetic nephropathy. Moreover, various endogenous vasoconstrictors are also upregulated in diabetic nephropathy. VED has been shown to be involved in diabetic nephropathy by inducing nodular glomerulosclerosis followed by glomerular basement membrane thickness and mesangial expansion, which ultimately decline glomerular filtration rate (GFR). Thus it is suggested that diabetes-induced VED could be one of the culprits involved in the pathogenesis of diabetic nephropathy.

  1. Genistein Attenuates Vascular Endothelial Impairment in Ovariectomized Hyperhomocysteinemic Rats

    Directory of Open Access Journals (Sweden)

    Panpan Zhen

    2012-01-01

    Full Text Available Hyperhomocysteinemia (HHcy is a well-known independent risk factor for vascular diseases in the general population. This study was to explore the effect of genistein (GST, a natural bioactive compound derived from legumes, on HHcy-induced vascular endothelial impairment in ovariectomized rats in vivo. Thirty-two adult female Wistar rats were assigned randomly into four groups (n=8: (a Con: control; (b Met: 2.5% methionine diet; (c OVX + Met: ovariectomy + 2.5% methionine diet; (d OVX + Met + GST: ovariectomy + 2.5% methionine diet + supplementation with genistein. After 12 wk of different treatment, the rats' blood, toracic aortas and liver samples were collected for analysis. Results showed that high-methionine diet induced both elevation of plasma Hcy and endothelial dysfunction, and ovariectomy deteriorated these injuries. Significant improvement of both functional and morphological changes of vascular endothelium was observed in OVX + Met + GST group; meanwhile the plasma Hcy levels decreased remarkably. There were significant elevations of plasma ET-1 and liver MDA levels in ovariectomized HHcy rats, and supplementation with genistein could attenuate these changes. These results implied that genistein could lower the elevated Hcy levels, and prevent the development of endothelial impairment in ovariectomized HHcy rats. This finding may shed a novel light on the anti-atherogenic activities of genistein in HHcy patients.

  2. Vascular endothelial growth factor A and vascular endothelial growth factor receptor 2 expression in non-small cell lung cancer patients: relation to prognosis

    DEFF Research Database (Denmark)

    Bonnesen, Barbara; Pappot, Helle; Holmstav, Julie;

    2009-01-01

    elements in neoplastic cells and their microenvironment have recently been and are continuously developed including drugs inhibiting the angiogenic system. Angiogenic factor vascular endothelial growth factor (VEGF) and its receptor vascular endothelial growth factor receptor 2 (VEGFR2) seem to play key...

  3. Healing arterial ulcers: Endothelial lining regeneration upon vascular denudation injury.

    Science.gov (United States)

    McDonald, Austin I; Iruela-Arispe, M Luisa

    2015-09-01

    Thrombosis and restenosis are the most prevalent late complications of coronary artery stenting. Current standards of clinical care focus on prevention of smooth muscle cell proliferation by the use of drug-eluting stents able to release anti-proliferative drugs. Unfortunately, these drugs also block endothelial cell proliferation and, in this manner, prevent recovery of endothelial cell coverage. Continued lack of endothelial repair leaves the root cause of thrombosis and restenosis unchanged, creating a vicious cycle where drug-mediated prevention of restenosis simultaneously implies promotion of thrombosis. In this issue of Vascular Pharmacology, Hussner and colleagues provide in vitro evidence and a mechanistic basis for the use of atorvastatin in stents as a way to bypass this roadblock. Here we review the pathological mechanisms and therapeutic approaches to restore flow in occluded arteries. We argue that rational design of drug eluting stents should focus on specific inhibition of smooth muscle cell proliferation with concurrent stimulation of endothelial regeneration. We comment on the current poor understanding of the cellular and molecular regulation of endothelial cell proliferation in the context of a functional artery, and on the pitfalls of extrapolating from the well-studied process of neovascularization by sprouting vessel formation.

  4. Vascular Endothelial Growth Factor from Embryonic Status to Cardiovascular Pathology

    Directory of Open Access Journals (Sweden)

    Mohsen Azimi-Nezhad

    2014-05-01

    Full Text Available Vascular endothelial growth factor (VEGF is a multifunctional cytokine with distinct functions in angiogenesis, lymphangiogenesis, vascular permeability, and hematopoiesis. VEGF is a highly conserved, disulfide-bonded dimeric glycoprotein of 34 to 45 kDa produced by several cell types including fibroblasts, neutrophils, endothelial cells, and peripheral blood mononuclear cells, particularly T lymphocytes and macrophages. Six VEGF isoforms are generated as a result of alternative splicing from a single VEGF gene, consisting of 121, 145, 165, 183, 189, or 206 amino acids. VEGF121, VEGF145, and VEGF165 are secreted whereas VEGF183, VEGF189, and VEGF206 are cell membrane-bound. VEGF145 has a key role during the vascularization of the human ovarian follicle and corpus luteum, in the placentation and embryonic periods, and in bone and wound healing, while VEGF165 is the most abundant and biologically active isoform. VEGF has been linked with a number of vascular pathologies including cardiovascular diseases such ischemic heart disease, heart failure, stroke, and diabetes and its related complications. In this review we aimed to present some important roles of VEGF in a number of clinical issues and indicate its involvement in several phenomena from the initial steps of the embryonic period to cardiovascular diseases.

  5. Effect of agmatine on experimental vascular endothelial dysfunction.

    Science.gov (United States)

    Nader, M A; Gamiel, N M; El-Kashef, H; Zaghloul, M S

    2016-05-01

    This study was designed to investigate the effect of agmatine sulfate (AG, CAS2482-00-0) in nicotine (NIC)-induced vascular endothelial dysfunction (VED) in rabbits. NIC was administered to produce VED in rabbits with or without AG for 6 weeks. Serum lipid profile, serum thiobarbituric acid reactive substances, reduced glutathione, superoxide dismutase generation, serum nitrite/nitrate, serum vascular cellular adhesion molecule-1 (VCAM-1), and aortic nuclear factor κB (NF-κB) levels were analyzed.Treatment with AG markedly improves lipid profile and prevented NIC-induced VED and oxidative stress. The mechanism of AG in improving NIC-induced VED may be due to the significant reduction in serum VCAM-1 levels and aortic NF-κB. Thus, it may be concluded that AG reduces the oxidative stress, nitric oxide production, VCAM-1 levels, and aortic NF-κB expression, thereby consequently improving the integrity of vascular endothelium.

  6. Preparation and features of polycaprolactone vascular grafts with the incorporated vascular endothelial growth factor

    Energy Technology Data Exchange (ETDEWEB)

    Sevostyanova, V. V., E-mail: sevostyanova.victoria@gmail.com; Khodyrevskaya, Y. I.; Glushkova, T. V.; Antonova, L. V.; Kudryavtseva, Y. A.; Barbarash, O. L.; Barbarash, L. S. [Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo (Russian Federation)

    2015-10-27

    The development of tissue-engineered small-diameter vascular grafts is an urgent issue in cardiovascular surgery. In this study, we assessed how the incorporation of the vascular endothelial growth factor (VEGF) affects morphological and mechanical properties of polycaprolactone (PCL) vascular grafts along with its release kinetics. Vascular grafts were prepared using two-phase electrospinning. In pursuing our aims, we performed scanning electron microscopy, mechanical testing, and enzyme-linked immunosorbent assay. Our results demonstrated the preservation of a highly porous structure and improvement of PCL/VEGF scaffold mechanical properties as compared to PCL grafts. A prolonged VEGF release testifies the use of this construct as a scaffold for tissue-engineered vascular grafts.

  7. Hypoxia, leptin, and vascular endothelial growth factor stimulate vascular endothelial cell differentiation of human adipose tissue-derived stem cells.

    Science.gov (United States)

    Bekhite, Mohamed M; Finkensieper, Andreas; Rebhan, Jennifer; Huse, Stephanie; Schultze-Mosgau, Stefan; Figulla, Hans-Reiner; Sauer, Heinrich; Wartenberg, Maria

    2014-02-15

    The plasticity of human adipose tissue-derived stem cells (hASCs) is promising, but differentiation in vitro toward endothelial cells is poorly understood. Flow cytometry demonstrated that hASCs isolated from excised fat tissue were positive for CD29, CD44, CD70, CD90, CD105, and CD166 and negative for the endothelial marker CD31, and the hematopoietic cell markers CD34 and CD133. hASCs differentiated into adipocytes after cultivation in adipogenic medium. Exposure of hASCs for 10 days under hypoxia (3% oxygen) in combination with leptin increased the percentage of CD31(+) endothelial cells as well as CD31, VE-Cadherin, Flk-1, Tie2, von Willebrand factor, and endothelial cell nitric oxide synthase mRNA expression. This was enhanced on co-incubation of vascular endothelial growth factor (VEGF) and leptin, whereas VEGF alone was not sufficient. Moreover, hASCs cultured on a matrigel surface under hypoxia/VEGF/leptin, showed a stable branching network. Hypoxic conditions significantly decreased apoptosis as evaluated by cleaved caspase-3, and increased prolyl hydroxylase domain 3 mRNA expression. Hypoxia increased expression of VEGF as well as leptin transcripts, which were significantly inhibited on co-incubation with either VEGF or leptin or a combination of both. Furthermore, leptin treatment of hypoxic cells increased the expression of the long/signaling form of the leptin receptor (ObRL), which was augmented on co-incubation with VEGF. The observed endothelial differentiation was dependent on the Akt pathway, as co-administration with Akt inhibitor abolished the observed effects. In conclusion, our data demonstrate that hASCs can be efficiently differentiated to endothelial cells by mimicking the hypoxic and pro-angiogenic microenvironment of adipose tissue.

  8. Regulation of vascular endothelial junction stability and remodeling through Rap1-Rasip1 signaling.

    Science.gov (United States)

    Wilson, Christopher W; Ye, Weilan

    2014-01-01

    agents targeting this pathway have shown efficacy in a number of diseases. (5)(-) (9) Blood vessels must have a sufficient degree of integrity so as to not allow indiscriminate leak of plasma proteins and blood cells into the underlying tissue. However, vessels must be able to sense their environment, respond to local conditions, and mediate the regulated passage of protein, fluid, and cells. For example, endothelial cells are the primary point of attachment for immune cells leaving the blood stream and entering tissue, and leukocytes subsequently migrate either through the endothelial cell body itself (the transcellular route), or through transient disassembly of cell-cell junctions (the paracellular route). (10) Precise regulation of endothelial junctions is critical to the proper maintenance of vascular integrity and related processes, and disruption of vascular cell-cell contacts is an underlying cause or contributor to numerous pathologies such as cerebral cavernous malformations (CCM) and hereditary hemorrhagic telangiectasia (HHT). (11)(-) (13) Understanding the basic mechanisms of endothelial junction formation and maintenance will therefore lead to a greater chance of success of therapeutic intervention in these pathologic conditions, especially in instances where targeting of VEGF signaling is insufficient to resolve vascular abnormalities.

  9. Opioid-induced proliferation of vascular endothelial cells

    Directory of Open Access Journals (Sweden)

    Sandra Leo

    2009-05-01

    Full Text Available Sandra Leo1,2, Rony Nuydens1, Theo F Meert11Pain and Neurology, CNS Department, Johnson and Johnson Pharmaceutical Research and Development, a division of Janssen Pharmaceutica N.V, Beerse, Belgium; 2Laboratory of Biological Psychology, University of Leuven, Leuven, BelgiumAbstract: Angiogenesis is an important issue in cancer research and opioids are often used to treat pain in cancer patients. Therefore it is important to know if the use of opioids is associated with an aberrant stimulation of tumor growth triggered by the stimulation of angiogenesis in cancer patients. Some studies in the literature have suggested the presence of the μ3 opioid receptor, known as the receptor for many opioids, on endothelial cells, which are key players in the process of angiogenesis. In this study we used endothelial cells known to express the μ3 opioid receptor (MOR3, to evaluate the effects of morphine on angiogenesis. We first investigated the effect of morphine on the proliferation of endothelial cells. We showed that morphine is able to stimulate vascular endothelial cell proliferation in vitro. This effect of morphine is mediated by the mitogen-activated protein kinase (MAPK pathway as pre-treatment with PD98059 inhibited this excessive proliferation. Because previous studies indicated nitric oxide (NO as a downstream messenger we investigated the role of NO in the aberrant proliferation of endothelial cells. Our data could not confirm these findings using intracellular NO measurements and quantitative fluorescence microscopy. The potential use and pitfalls of opioids in cancer patients is discussed in light of these negative findings. Keywords: endothelial cells, morphine, cell proliferation, MAPK, nitric oxide, μ3 opioid receptor, angiogenesis

  10. Neuropilin-1 mediates vascular permeability independently of vascular endothelial growth factor receptor-2 activation.

    Science.gov (United States)

    Roth, Lise; Prahst, Claudia; Ruckdeschel, Tina; Savant, Soniya; Weström, Simone; Fantin, Alessandro; Riedel, Maria; Héroult, Mélanie; Ruhrberg, Christiana; Augustin, Hellmut G

    2016-04-26

    Neuropilin-1 (NRP1) regulates developmental and pathological angiogenesis, arteriogenesis, and vascular permeability, acting as a coreceptor for semaphorin 3A (Sema3A) and the 165-amino acid isoform of vascular endothelial growth factor A (VEGF-A165). NRP1 is also the receptor for the CendR peptides, a class of cell- and tissue-penetrating peptides with a specific R-x-x-R carboxyl-terminal motif. Because the cytoplasmic domain of NRP1 lacks catalytic activity, NRP1 is mainly thought to act through the recruitment and binding to other receptors. We report here that the NRP1 intracellular domain mediates vascular permeability. Stimulation with VEGF-A165, a ligand-blocking antibody, and a CendR peptide led to NRP1 accumulation at cell-cell contacts in endothelial cell monolayers, increased cellular permeability in vitro and vascular leakage in vivo. Biochemical analyses, VEGF receptor-2 (VEGFR-2) silencing, and the use of a specific VEGFR blocker established that the effects induced by the CendR peptide and the antibody were independent of VEGFR-2. Moreover, leakage assays in mice expressing a mutant NRP1 lacking the cytoplasmic domain revealed that this domain was required for NRP1-induced vascular permeability in vivo. Hence, these data define a vascular permeability pathway mediated by NRP1 but independent of VEGFR-2 activation.

  11. l-arginine and l-NMMA for assessing cerebral endothelial dysfunction in ischaemic cerebrovascular disease: A systematic review.

    Science.gov (United States)

    Karlsson, William K; Sørensen, Caspar G; Kruuse, Christina

    2017-01-01

    Endothelial dysfunction (ED), in particular cerebral ED, may be an essential biomarker for ischaemic cerebrovascular disease. However, there is no consensus on methods to best estimate cerebral ED. In this systematic review, we evaluate the use of l-arginine and N(G) -monomethyl-l-arginine (l-NMMA) for assessment of cerebral ED. A systematic search of PubMed, EMBASE and the Cochrane Library was done. We included studies investigating cerebrovascular response to l-arginine or l-NMMA in human subjects with vascular risk factors or ischaemic cerebrovascular disease. Seven studies (315 subjects) were eligible according to inclusion and exclusion criteria. Studies investigated the effect of age (n=2), type 2 diabetes mellitus (DM) (n=1), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (n=1), leukoaraiosis (n=1), and prior ischaemic stroke or transient ischaemic attack (TIA) (n=2) on cerebral ED. Most studies applied transcranial Doppler to quantify cerebral ED. Endothelium-dependent vasodilatation (EDV) induced by l-arginine was impaired in elderly and subjects with leukoaraiosis, but enhanced in CADASIL patients. Studies including subjects with prior ischaemic stroke or TIA reported both enhanced and impaired EDV to l-arginine. Responses to l-NMMA deviated between subjects with type 2 DM and the elderly. We found only few studies investigating cerebral endothelial responses to l-arginine and l-NMMA in subjects with vascular risk factors or ischaemic cerebrovascular disease. Inconsistencies in results were most likely due to variations in methods and included subject populations. In order to use cerebral ED as a prognostic marker, further studies are required to evaluate the association to cerebrovascular disease.

  12. Atrial natriuretic peptide prevents cancer metastasis through vascular endothelial cells.

    Science.gov (United States)

    Nojiri, Takashi; Hosoda, Hiroshi; Tokudome, Takeshi; Miura, Koichi; Ishikane, Shin; Otani, Kentaro; Kishimoto, Ichiro; Shintani, Yasushi; Inoue, Masayoshi; Kimura, Toru; Sawabata, Noriyoshi; Minami, Masato; Nakagiri, Tomoyuki; Funaki, Soichiro; Takeuchi, Yukiyasu; Maeda, Hajime; Kidoya, Hiroyasu; Kiyonari, Hiroshi; Shioi, Go; Arai, Yuji; Hasegawa, Takeshi; Takakura, Nobuyuki; Hori, Megumi; Ohno, Yuko; Miyazato, Mikiya; Mochizuki, Naoki; Okumura, Meinoshin; Kangawa, Kenji

    2015-03-31

    Most patients suffering from cancer die of metastatic disease. Surgical removal of solid tumors is performed as an initial attempt to cure patients; however, surgery is often accompanied with trauma, which can promote early recurrence by provoking detachment of tumor cells into the blood stream or inducing systemic inflammation or both. We have previously reported that administration of atrial natriuretic peptide (ANP) during the perioperative period reduces inflammatory response and has a prophylactic effect on postoperative cardiopulmonary complications in lung cancer surgery. Here we demonstrate that cancer recurrence after curative surgery was significantly lower in ANP-treated patients than in control patients (surgery alone). ANP is known to bind specifically to NPR1 [also called guanylyl cyclase-A (GC-A) receptor]. In mouse models, we found that metastasis of GC-A-nonexpressing tumor cells (i.e., B16 mouse melanoma cells) to the lung was increased in vascular endothelium-specific GC-A knockout mice and decreased in vascular endothelium-specific GC-A transgenic mice compared with control mice. We examined the effect of ANP on tumor metastasis in mice treated with lipopolysaccharide, which mimics systemic inflammation induced by surgical stress. ANP inhibited the adhesion of cancer cells to pulmonary arterial and micro-vascular endothelial cells by suppressing the E-selectin expression that is promoted by inflammation. These results suggest that ANP prevents cancer metastasis by inhibiting the adhesion of tumor cells to inflamed endothelial cells.

  13. Gamma knife irradiation increases cerebral endothelial expression of intercellular adhesion molecule 1 and E-selectin.

    Science.gov (United States)

    Sharp, Christopher D; Jawahar, Ajay; Warren, April C; Elrod, John W; Nanda, Anil; Alexander, J Steven

    2003-07-01

    Alterations in multiple functions of the microvasculature occur in response to gamma irradiation and are thought to contribute to radiation-induced end organ damage by inducing inflammatory responses, particularly leukocyte infiltration into the affected area. Endothelial cell adhesion molecules (ECAMs) mediate leukocyte adhesion and migration. Here, we validate a method to study the effect of Leksell gamma knife stereotactic radiosurgery on the expression of ECAMs on human cerebral endothelium at 0, 24, 48, and 72 hours after irradiation. A human brain endothelial cell line (IHEC) was cultured on 12-mm coverslips and subjected to 50 Gy of collimated gamma irradiation with the Leksell gamma knife (Elekta Instruments, Inc., Atlanta, GA). Lactate dehydrogenase release was measured at 24, 48, and 72 hours after irradiation and caspase-3 at 24, 48, 72, 96, and 120 hours. ECAM expression was measured at postirradiation intervals of 0, 24, 48, and 72 hours by cell enzyme-linked immunoabsorbent assay. We used a cell irradiator composed of two chambers. The upper chamber holds the coverslips firmly in place while they are immersed in media. The lower chamber is connected to a peristaltic pump, which pumps water into the chamber and maintains the media in the upper chamber at 37 degrees C through convection. None of the ECAMs tested was significantly elevated compared with the control basally. Twenty-four hours after irradiation, intercellular adhesion molecule 1 was significantly elevated on brain endothelial cells but there was no significant elevation of E-selectin. Vascular cell adhesion molecule 1 was increased slightly but not significantly and decreased at 48 hours. At 72 hours, E-selectin expression was significantly increased; intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 were not altered relative to sham controls. Increased ECAM expression and lactate dehydrogenase release support the idea that the cerebral microvasculature undergoes an

  14. Matrix metalloproteinase-9 mediates post-hypoxic vascular pruning of cerebral blood vessels by degrading laminin and claudin-5.

    Science.gov (United States)

    Boroujerdi, Amin; Welser-Alves, Jennifer V; Milner, Richard

    2015-07-01

    Vascular remodeling involves a highly coordinated break-down and build-up of the vascular basal lamina and inter-endothelial tight junction proteins. In light of the important role of matrix metalloproteinases (MMPs) in tissue remodeling, the goal of this study was to examine the role of MMP-9 in remodeling of cerebral blood vessels, both in hypoxia-induced angiogenesis and in the vascular pruning that accompanies the switch from hypoxia back to normoxia. In a chronic mild hypoxia model of cerebrovascular remodeling, gel zymography revealed that MMP-9 levels were increased, both during hypoxic-induced angiogenesis and in the post-hypoxic pruning response. Interestingly, compared to wild-type mice, MMP-9 KO mice showed no alteration in hypoxic-induced angiogenesis, but did show marked delay in post-hypoxic vascular pruning. In wild-type mice, vascular pruning was associated with fragmentation of vascular laminin and the tight junction protein claudin-5, while this process was markedly attenuated in MMP-9 KO mice. In vitro experiments showed that hypoxia stimulated MMP-9 expression in brain endothelial cells but not pericytes. These results show that while MMP-9 is not essential for hypoxic-induced cerebral angiogenesis, it plays an important role in post-hypoxic vascular pruning by degrading laminin and claudin-5.

  15. Expression of vascular endothelial growth factor in malignant mesothelioma.

    Science.gov (United States)

    Aoe, Keisuke; Hiraki, Akio; Tanaka, Takehiro; Gemba, Ken-Ichi; Taguchi, Koji; Murakami, Tomoyuki; Sueoka, Naoko; Kamei, Toshiaki; Ueoka, Hiroshi; Sugi, Kazuro; Yoshino, Tadashi; Kishimoto, Takumi

    2006-01-01

    Malignant mesothelioma is the most common primary pleural neoplasm. Angiogenesis is an important component of a variety of pathological processes, including carcinogenesis and tumor metastases. Vascular endothelial growth factor (VEGF) is the most potent known endothelial, cell specific mitogen. The authors assessed the relation between VEGF expression and clinicopathological variables or overall survival, in malignant mesothelioma. We studied 37 patients with malignant pleural mesothelioma and found that 36 out of 37 (97.3%) malignant mesothelioma samples were stained positively for VEGF. An increased expression of VEGF was observed in the epithelioid type compared with the other histological types of malignant mesothelioma, including the biphasic and sarcomatoid types. No statistically significant association was observed between VEGF expression and gender, age, or clinical stage. Furthermore, the expression of VEGF did not impact on the survival of patients with malignant mesothelioma. Although VEGF expression might be important for tumor development and maintenance, it was not identified as a prognostic factor in malignant mesothelioma.

  16. Local Augmented Angiotensinogen Secreted from Apoptotic Vascular Endothelial Cells Is a Vital Mediator of Vascular Remodelling.

    Directory of Open Access Journals (Sweden)

    Shyh-Jong Wu

    Full Text Available Vascular remodelling is a critical vasculopathy found in atheromatous diseases and allograft failures. The local renin angiotensin system (RAS has been implicated in vascular remodelling. However, the mechanisms by which the augmented local RAS is associated with the initial event of endothelial cell apoptosis in injured vasculature remain undefined. We induced the apoptosis of human umbilical vein endothelial cells (HUVECs and vascular smooth muscle cells (VSMCs through serum starvation (SS. After the cells were subjected to SS, we found that the mRNA expression of angiotensinogen (AGT was increased by >3-fold in HUVECs and by approximately 2.5-fold in VSMCs. In addition, the expression of angiotensin-converting enzyme (ACE mRNA was increased in VSMCs but decreased to 50% in HUVECs during the same apoptotic process. Increases in the expression of AGT protein and angiotensin II (Ang II were found in a serum-free medium conditioned by HUVECs (SSC. The increased Ang II was suppressed using lisinopril (an ACE inhibitor treatment. Moreover, the activation of ERK1/2 induced by the SSC in VSMCs was also suppressed by losartan. In conclusion, we first demonstrated that the augmented AGT released from apoptotic endothelial cells acts as a vital progenitor of Ang II to accelerate vascular remodelling, and we suggest that blocking local augmented Ang II might be an effective strategy for restraining intimal hyperplasia.

  17. Blockade of Vascular Endothelial Growth Factor Receptor 1 Prevents Inflammation and Vascular Leakage in Diabetic Retinopathy

    Directory of Open Access Journals (Sweden)

    Jianbo He

    2015-01-01

    Full Text Available Diabetic retinopathy (DR is a leading cause of blindness in working age adults. The objective of this study is to investigate the effects of vascular endothelial growth factor receptor 1 (VEGFR1 blockade on the complications of DR. Experimental models of diabetes were induced with streptozotocin (STZ treatment or Insulin2 gene mutation (Akita in mice. Protein expression and localization were examined by western blots (WB and immunofluorescence (IF. mRNA expression was quantified by PCR array and real-time PCR. The activity of VEGFR1 signaling was blocked by a neutralizing antibody called MF1. Vascular leakage was evaluated by measuring the leakage of [3H]-mannitol tracer into the retina and the IF staining of albumin. VEGFR1 blockade significantly inhibited diabetes-related vascular leakage, leukocytes-endothelial cell (EC adhesion (or retinal leukostasis, expression of intercellular adhesion molecule- (ICAM- 1 protein, abnormal localization and degeneration of the tight junction protein zonula occludens- (ZO- 1, and the cell adhesion protein vascular endothelial (VE cadherin. In addition, VEGFR1 blockade interfered with the gene expression of 10 new cytokines and chemokines: cxcl10, il10, ccl8, il1f6, cxcl15, ccl4, il13, ccl6, casp1, and ccr5. These results suggest that VEGFR1 mediates complications of DR and targeting this signaling pathway represents a potential therapeutic strategy for the prevention and treatment of DR.

  18. Involvement of Rho-kinase in experimental vascular endothelial dysfunction.

    Science.gov (United States)

    Shah, Dhvanit I; Singh, Manjeet

    2006-02-01

    The present study has been designed to investigate the effect of fasudil (Rho-kinase inhibitor) in diabetes mellitus (DM) and hyperhomocyteinemia (HHcy) induced vascular endothelial dysfunction (VED). Streptozotocin (55 mg kg(-1), i.v., once only) and methionine (1.7% w/w, p.o., daily for 4 weeks) were administered to rats to produce DM (serum glucose >140 mg dl(-1)) and HHcy (serum homocysteine >10 microM) respectively. VED was assessed using isolated aortic ring, electron microscopy of thoracic aorta, and serum concentration of nitrite/nitrate. Serum thiobarbituric acid reactive substances (TBARS) concentration was estimated to assess oxidative stress. Atorvastatin has been employed in the present study as standard agent to improve vascular endothelial dysfunction. Fasudil (15 mg kg(-1) and 30 mg kg(-1), p.o., daily) and atorvastatin (30 mg kg(-1), p.o., daily) treatments significantly attenuated increase in serum glucose and homocysteine but their concentrations remained markedly higher than sham control value. Fasudil and atorvastatin treatments markedly prevented DM and HHcy-induced (i) attenuation of acetylcholine induced endothelium-dependent relaxation, (ii) impairment of vascular endothelial lining, (iii) decrease in serum nitrite/nitrate concentration, and (iv) increase in serum TBARS. It may be concluded that fasudil prevented DM and HHcy-induced VED partially by decreasing serum glucose and homocysteine concentration due to inhibition of Rho-kinase. Moreover, inhibition of Rho-kinase by fasudil and consequent prevention of oxidative stress may have directly improved VED in diabetic and hyperhomocysteinemic rats. The Rho-kinase appears to be a pivotal target site involved in DM and HHcy-induced VED.

  19. Glycoconjugates and Related Molecules in Human Vascular Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Norihiko Sasaki

    2013-01-01

    Full Text Available Vascular endothelial cells (ECs form the inner lining of blood vessels. They are critically involved in many physiological functions, including control of vasomotor tone, blood cell trafficking, hemostatic balance, permeability, proliferation, survival, and immunity. It is considered that impairment of EC functions leads to the development of vascular diseases. The carbohydrate antigens carried by glycoconjugates (e.g., glycoproteins, glycosphingolipids, and proteoglycans mainly present on the cell surface serve not only as marker molecules but also as functional molecules. Recent studies have revealed that the carbohydrate composition of the EC surface is critical for these cells to perform their physiological functions. In this paper, we consider the expression and functional roles of endogenous glycoconjugates and related molecules (galectins and glycan-degrading enzymes in human ECs.

  20. Cerebral endothelial dysfunction in reversible cerebral vasoconstriction syndrome: a case-control study.

    Science.gov (United States)

    Choi, Hyun Ah; Lee, Mi Ji; Chung, Chin-Sang

    2017-12-01

    The aim of this study is to investigate cerebral endothelial dysfunction in patients with reversible cerebral vasoconstriction syndrome (RCVS). We prospectively recruited patients with RCVS, age-matched controls with episodic migraine, and age-matched healthy controls at Samsung Medical Center from Apr 2015 to Jul 2016. All participants underwent transcranial Doppler evaluation, with a breath-holding maneuver, for the evaluation of bilateral middle cerebral arteries (MCAs), posterior cerebral arteries (PCAs), and the basilar artery (BA). The breath-holding index (BHI) was used to measure cerebral endothelium-dependent vasodilation. Follow-up BHIs were recorded in selected patients with RCVS after 3 months. A total of 84 subjects were recruited for this study (n = 28 in each group of RCVS, episodic migraine, and healthy control; mean age, 49.8 years). The RCVS group showed lower BHIs in all basal arteries, in comparison to healthy controls (p < 0.001, 0.009 for bilateral MCAs, p < 0.001 and 0.028 for bilateral PCAs, and p = 0.060 for the BA). Compared to migraineurs, RCVS patients had lower BHIs only in the anterior circulation (p = 0.002 and 0.038 for bilateral MCAs; p = 0.069 and 0.247 for bilateral PCAs; p = 0.120 for the BA). Of the 10 patients who had follow-up BHIs at 3 months, 7 showed complete normalization, while three did not. Cerebral endothelial function is impaired in a widespread distribution in RCVS. Its role in the pathogenesis and clinical outcome of RCVS should be determined in further studies.

  1. Mesoporous bioactive glass scaffolds for efficient delivery of vascular endothelial growth factor.

    Science.gov (United States)

    Wu, Chengtie; Fan, Wei; Chang, Jiang; Xiao, Yin

    2013-09-01

    In this article, we, for the first time, investigated mesoporous bioactive glass scaffolds for the delivery of vascular endothelial growth factor. We have found that mesoporous bioactive glass scaffolds have significantly higher loading efficiency and more sustained release of vascular endothelial growth factor than non-mesoporous bioactive glass scaffolds. In addition, vascular endothelial growth factor delivery from mesoporous bioactive glass scaffolds has improved the viability of endothelial cells. The study has suggested that mesopore structures in mesoporous bioactive glass scaffolds play an important role in improving the loading efficiency, decreasing the burst release, and maintaining the bioactivity of vascular endothelial growth factor, indicating that mesoporous bioactive glass scaffolds are an excellent carrier of vascular endothelial growth factor for potential bone tissue engineering applications.

  2. Erythropoietin employs cell longevity pathways of SIRT1 to foster endothelial vascular integrity during oxidant stress.

    Science.gov (United States)

    Hou, Jinling; Wang, Shaohui; Shang, Yan Chen; Chong, Zhao Zhong; Maiese, Kenneth

    2011-08-01

    Given the cytoprotective ability of erythropoietin (EPO) in cerebral microvascular endothelial cells (ECs) and the invaluable role of ECs in the central nervous system, it is imperative to elucidate the cellular pathways for EPO to protect ECs against brain injury. Here we illustrate that EPO relies upon the modulation of SIRT1 (silent mating type information regulator 2 homolog 1) in cerebral microvascular ECs to foster cytoprotection during oxygen-glucose deprivation (OGD). SIRT1 activation which results in the inhibition of apoptotic early membrane phosphatidylserine (PS) externalization and subsequent DNA degradation during OGD becomes a necessary component for EPO protection in ECs, since inhibition of SIRT1 activity or diminishing its expression by gene silencing abrogates cell survival supported by EPO during OGD. Furthermore, EPO promotes the subcellular trafficking of SIRT1 to the nucleus which is necessary for EPO to foster vascular protection. EPO through SIRT1 averts apoptosis through activation of protein kinase B (Akt1) and the phosphorylation and cytoplasmic retention of the forkhead transcription factor FoxO3a. SIRT1 through EPO activation also utilizes mitochondrial pathways to prevent mitochondrial depolarization, cytochrome c release, and Bad, caspase 1, and caspase 3 activation. Our work identifies novel pathways for EPO in the vascular system that can govern the activity of SIRT1 to prevent apoptotic injury through Akt1, FoxO3a phosphorylation and trafficking, mitochondrial membrane permeability, Bad activation, and caspase 1 and 3 activities in ECs during oxidant stress.

  3. Studies on Treatment of Cerebral Vascular Disease with Integrative Medicine

    Institute of Scientific and Technical Information of China (English)

    孙怡; 韩景献; 谢道珍; 李如奎; 高利; 许健鹏

    2003-01-01

    @@Cerebral vascular disease (CVD) also called the cerebral stroke or wind stroke. There are two common types in clinic, that is, thrombotic CVD and hemorrhagic CVD. CVD has both a high incidence rate and a high mortality rate. It has become the most dangerous factor that costs the lives of the urban population in our country. People of different age groups can develop this kind of disease, and the morbidity rate increases dramatically for those middle-aged in recent years. At present, the harms done by CVD to the human heath are more prominent.

  4. Telmisartan Activates Endothelial Nitric Oxide Synthase via Ser1177 Phosphorylation in Vascular Endothelial Cells

    Science.gov (United States)

    Myojo, Masahiro; Nagata, Daisuke; Fujita, Daishi; Kiyosue, Arihiro; Takahashi, Masao; Satonaka, Hiroshi; Morishita, Yoshiyuki; Akimoto, Tetsu; Nagai, Ryozo; Komuro, Issei; Hirata, Yasunobu

    2014-01-01

    Because endothelial nitric oxide synthase (eNOS) has anti-inflammatory and anti-arteriosclerotic functions, it has been recognized as one of the key molecules essential for the homeostatic control of blood vessels other than relaxation of vascular tone. Here, we examined whether telmisartan modulates eNOS function through its pleiotropic effect. Administration of telmisartan to mice significantly increased the phosphorylation level of eNOS (Ser1177) in the aortic endothelium, but administration of valsartan had no effect. Similarly, telmisartan treatment of human umbilical vein endothelial cells significantly increased the phosphorylation levels of AMP-activated protein kinase (Thr172) and eNOS and the concentration of intracellular guanosine 3′,5′-cyclic monophosphate (cGMP). Furthermore, pretreatment with a p38 mitogen-activated protein kinase (p38 MAPK) inhibitor suppressed the increased phosphorylation level of eNOS and intracellular cGMP concentration. These data show that telmisartan increases eNOS activity through Ser1177 phosphorylation in vascular endothelial cells mainly via p38 MAPK signaling. PMID:24827148

  5. Telmisartan activates endothelial nitric oxide synthase via Ser1177 phosphorylation in vascular endothelial cells.

    Directory of Open Access Journals (Sweden)

    Masahiro Myojo

    Full Text Available Because endothelial nitric oxide synthase (eNOS has anti-inflammatory and anti-arteriosclerotic functions, it has been recognized as one of the key molecules essential for the homeostatic control of blood vessels other than relaxation of vascular tone. Here, we examined whether telmisartan modulates eNOS function through its pleiotropic effect. Administration of telmisartan to mice significantly increased the phosphorylation level of eNOS (Ser1177 in the aortic endothelium, but administration of valsartan had no effect. Similarly, telmisartan treatment of human umbilical vein endothelial cells significantly increased the phosphorylation levels of AMP-activated protein kinase (Thr172 and eNOS and the concentration of intracellular guanosine 3',5'-cyclic monophosphate (cGMP. Furthermore, pretreatment with a p38 mitogen-activated protein kinase (p38 MAPK inhibitor suppressed the increased phosphorylation level of eNOS and intracellular cGMP concentration. These data show that telmisartan increases eNOS activity through Ser1177 phosphorylation in vascular endothelial cells mainly via p38 MAPK signaling.

  6. Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling.

    Science.gov (United States)

    Zhou, Zinan; Tang, Alan T; Wong, Weng-Yew; Bamezai, Sharika; Goddard, Lauren M; Shenkar, Robert; Zhou, Su; Yang, Jisheng; Wright, Alexander C; Foley, Matthew; Arthur, J Simon C; Whitehead, Kevin J; Awad, Issam A; Li, Dean Y; Zheng, Xiangjian; Kahn, Mark L

    2016-04-07

    Cerebral cavernous malformations (CCMs) are common inherited and sporadic vascular malformations that cause strokes and seizures in younger individuals. CCMs arise from endothelial cell loss of KRIT1, CCM2 or PDCD10, non-homologous proteins that form an adaptor complex. How disruption of the CCM complex results in disease remains controversial, with numerous signalling pathways (including Rho, SMAD and Wnt/β-catenin) and processes such as endothelial-mesenchymal transition (EndMT) proposed to have causal roles. CCM2 binds to MEKK3 (refs 7, 8, 9, 10, 11), and we have recently shown that CCM complex regulation of MEKK3 is essential during vertebrate heart development. Here we investigate this mechanism in CCM disease pathogenesis. Using a neonatal mouse model of CCM disease, we show that expression of the MEKK3 target genes Klf2 and Klf4, as well as Rho and ADAMTS protease activity, are increased in the endothelial cells of early CCM lesions. By contrast, we find no evidence of EndMT or increased SMAD or Wnt signalling during early CCM formation. Endothelial-specific loss of Map3k3 (also known as Mekk3), Klf2 or Klf4 markedly prevents lesion formation, reverses the increase in Rho activity, and rescues lethality. Consistent with these findings in mice, we show that endothelial expression of KLF2 and KLF4 is increased in human familial and sporadic CCM lesions, and that a disease-causing human CCM2 mutation abrogates the MEKK3 interaction without affecting CCM complex formation. These studies identify gain of MEKK3 signalling and KLF2/4 function as causal mechanisms for CCM pathogenesis that may be targeted to develop new CCM therapeutics.

  7. Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signaling

    Science.gov (United States)

    Zhou, Zinan; Tang, Alan T.; Wong, Weng-Yew; Bamezai, Sharika; Goddard, Lauren M.; Shenkar, Robert; Zhou, Su; Yang, Jisheng; Wright, Alexander C.; Foley, Matthew; Arthur, J. Simon C.; Whitehead, Kevin J.; Awad, Issam A.; Li, Dean Y.; Zheng, Xiangjian; Kahn, Mark L.

    2016-01-01

    Cerebral cavernous malformations (CCMs) are common inherited and sporadic vascular malformations that cause stroke and seizures in younger individuals1. CCMs arise from endothelial cell loss of KRIT1, CCM2, or PDCD10, non-homologous proteins that form an adaptor complex2. How disruption of the CCM complex results in disease remains controversial, with numerous signaling pathways (including Rho3,4, SMAD5 and Wnt/β-catenin6) and processes such as endothelial-mesenchymal transition (EndMT)5 proposed to play causal roles. CCM2 binds MEKK37–11, and we have recently demonstrated that CCM complex regulation of MEKK3 is essential during vertebrate heart development12. Here, we investigate this mechanism in CCM disease pathogenesis. Using a neonatal mouse model of CCM disease, we find that expression of the MEKK3 target genes KLF2 and KLF4, as well as Rho and ADAMTS protease activity, are increased in the endothelial cells of early CCM lesions. In contrast, we find no evidence of EndMT or increased SMAD or Wnt signaling during early CCM formation. Endothelial-specific loss of Mekk3, Klf2, or Klf4 dramatically prevents lesion formation, reverses the increase in Rho activity, and rescues lethality. Consistent with these findings in mice, we demonstrate that endothelial expression of KLF2 and KLF4 is elevated in human familial and sporadic CCM lesions, and that a disease-causing human CCM2 mutation abrogates MEKK3 interaction without affecting CCM complex formation. These studies identify gain of MEKK3 signaling and KLF2/4 function as causal mechanisms for CCM pathogenesis that may be targeted to develop new CCM therapeutics. PMID:27027284

  8. Role of Mitochondria in Cerebral Vascular Function: Energy Production, Cellular Protection, and Regulation of Vascular Tone.

    Science.gov (United States)

    Busija, David W; Rutkai, Ibolya; Dutta, Somhrita; Katakam, Prasad V

    2016-06-13

    Mitochondria not only produce energy in the form of ATP to support the activities of cells comprising the neurovascular unit, but mitochondrial events, such as depolarization and/or ROS release, also initiate signaling events which protect the endothelium and neurons against lethal stresses via pre-/postconditioning as well as promote changes in cerebral vascular tone. Mitochondrial depolarization in vascular smooth muscle (VSM), via pharmacological activation of the ATP-dependent potassium channels on the inner mitochondrial membrane (mitoKATP channels), leads to vasorelaxation through generation of calcium sparks by the sarcoplasmic reticulum and subsequent downstream signaling mechanisms. Increased release of ROS by mitochondria has similar effects. Relaxation of VSM can also be indirectly achieved via actions of nitric oxide (NO) and other vasoactive agents produced by endothelium, perivascular and parenchymal nerves, and astroglia following mitochondrial activation. Additionally, NO production following mitochondrial activation is involved in neuronal preconditioning. Cerebral arteries from female rats have greater mitochondrial mass and respiration and enhanced cerebral arterial dilation to mitochondrial activators. Preexisting chronic conditions such as insulin resistance and/or diabetes impair mitoKATP channel relaxation of cerebral arteries and preconditioning. Surprisingly, mitoKATP channel function after transient ischemia appears to be retained in the endothelium of large cerebral arteries despite generalized cerebral vascular dysfunction. Thus, mitochondrial mechanisms may represent the elusive signaling link between metabolic rate and blood flow as well as mediators of vascular change according to physiological status. Mitochondrial mechanisms are an important, but underutilized target for improving vascular function and decreasing brain injury in stroke patients. © 2016 American Physiological Society. Compr Physiol 6:1529-1548, 2016.

  9. Interaction between human monocytes and vascular smooth muscle cells induces vascular endothelial growth factor expression.

    Science.gov (United States)

    Hojo, Y; Ikeda, U; Maeda, Y; Takahashi, M; Takizawa, T; Okada, M; Funayama, H; Shimada, K

    2000-05-01

    The objective of this study was to investigate whether synthesis of vascular endothelial growth factor (VEGF), a major mitogen for vascular endothelial cells, was induced by a cell-to-cell interaction between monocytes and vascular smooth muscle cells (VSMCs). Human VSMCs and THP-1 cells (human monocytoid cell) were cocultured. VEGF levels in the coculture medium were determined by enzyme-linked immunosorbent assay. Northern blot analysis of VEGF mRNA was performed using a specific cDNA probe. Immunohistochemistry was performed to determine which types of cell produce VEGF. Adding THP-1 cells to VSMCs for 24 h increased VEGF levels of the culture media, 8- and 10-fold relative to those of THP-1 cells and VSMCs alone, respectively. Northern blot analysis showed that VEGF mRNA expression was induced in the cocultured cells and peaked after 12 h. Immunohistochemistry disclosed that both types of cell in the coculture produced VEGF. Separate coculture experiments revealed that both direct contact and a soluble factor(s) contributed to VEGF production. Neutralizing anti-interleukin (IL)-6 antibody inhibited VEGF production by the coculture of THP-1 cells and VSMCs. A cell-to-cell interaction between monocytes and VSMCs induced VEGF synthesis in both types of cell. An IL-6 mediated mechanism is at least partially involved in VEGF production by the cocultures. Local VEGF production induced by a monocyte-VSMC interaction may play an important role in atherosclerosis and vascular remodeling.

  10. Cerebral vascular accident: some characteristics of occupational therapy evaluation forms.

    Science.gov (United States)

    Ottenbacher, K

    1980-04-01

    To determine areas most commonly evaluated by occupational therapists and to ascertain methods in which evaluative information is gathered, 35 evaluation forms currently employed by occupational therapists to assess dysfunction in patients with cerebral vascular accident were collected. Five general areas including motor function, sensory deficit, hadn function, activities of daily living, and visual perception were found to be most frequently listed on the forms. These areas were divided into sub areas to operationally define the information collected. Analysis revealed that the level of measurement most frequently employed by therapists to record evaluate findings was the descriptive level. There was a tendency to collect data at "higher" or more sophisticated levels of measurement in those areas evaluated most frequently. The findings are discussed in relation to professional competency concerns and the need to develop unique occupational therapy evaluative instruments for areas of practice such as cerebral vascular accident.

  11. Pediatric Stroke: The Importance of Cerebral Arteriopathy and Vascular Malformations

    OpenAIRE

    Beslow, Lauren A.; Jordan, Lori C

    2010-01-01

    Stroke is an important cause of neurologic morbidity in childhood. Population-based estimates of the annual incidence of childhood stroke range from 2 to 13 per 100,000 children. This article will review recent literature on both hemorrhagic and ischemic stroke in children with a focus on cerebral arteriopathy and vascular malformations as stroke risk factors. Additional risk factors include congenital heart disease, sickle cell disease, and hematologic abnormalities among others. Outcomes ar...

  12. Acupuncture Treatment of Depressive Syndromes after Cerebral Vascular Accidents

    Institute of Scientific and Technical Information of China (English)

    王海荣

    2002-01-01

    @@ Depressive syndrome is a common complication in cerebral vascular accidents (CVA), which accounts for 70% of the complications. A mild case of the syndrome is marked by grief, sleeping disturbance, weakened mental activities, worry, loss of interest, and irritability. A severe case may have worse symptoms and signs, except the above mentioned ones, such as anxiety, reduced appetite, hallucination, delusion, desperation, etc. The author has adopted acupuncture to treat depressive syndromes after CVA with good therapeutic result as reported in the following.

  13. KLF2 and KLF4 control endothelial identity and vascular integrity

    Science.gov (United States)

    Sangwung, Panjamaporn; Zhou, Guangjin; Nayak, Lalitha; Chan, E. Ricky; Kang, Dong-Won; Zhang, Rongli; Lu, Yuan; Sugi, Keiki; Fujioka, Hisashi; Shi, Hong; Lapping, Stephanie D.; Ghosh, Chandra C.; Higgins, Sarah J.; Parikh, Samir M.; Jain, Mukesh K.

    2017-01-01

    Maintenance of vascular integrity in the adult animal is needed for survival, and it is critically dependent on the endothelial lining, which controls barrier function, blood fluidity, and flow dynamics. However, nodal regulators that coordinate endothelial identity and function in the adult animal remain poorly characterized. Here, we show that endothelial KLF2 and KLF4 control a large segment of the endothelial transcriptome, thereby affecting virtually all key endothelial functions. Inducible endothelial-specific deletion of Klf2 and/or Klf4 reveals that a single allele of either gene is sufficient for survival, but absence of both (EC-DKO) results in acute death from myocardial infarction, heart failure, and stroke. EC-DKO animals exhibit profound compromise in vascular integrity and profound dysregulation of the coagulation system. Collectively, these studies establish an absolute requirement for KLF2/4 for maintenance of endothelial and vascular integrity in the adult animal. PMID:28239661

  14. Cerebral malaria is associated with low levels of circulating endothelial progenitor cells in African children.

    Science.gov (United States)

    Gyan, Ben; Goka, Bamenla Quarm; Adjei, George O; Tetteh, John K A; Kusi, Kwadwo Asamoah; Aikins, Anastasia; Dodoo, Daniel; Lesser, Martin L; Sison, Cristina P; Das, Sanchita; Howard, Marion E; Milbank, Elizabeth; Fischer, Kimberly; Rafii, Shahin; Jin, David; Golightly, Linnie M

    2009-04-01

    Damage to the cerebral microvasculature is a feature of cerebral malaria. Circulating endothelial progenitor cells are needed for microvascular repair. Based on this knowledge, we hypothesized that the failure to mobilize sufficient circulating endothelial progenitor cells to the cerebral microvasculature is a pathophysiologic feature of cerebral malaria. To test this hypothesis, we compared peripheral blood levels of CD34 (+)/VEGFR2(+) and CD34 (+)/CD133(+) cells and plasma levels of the chemokine stromal cell-derived growth factor 1 (SDF-1) in 214 children in Accra, Ghana. Children with cerebral malaria had lower levels of CD34 (+)/VEGFR2(+) and CD34 (+)/CD133(+) cells compared with those with uncomplicated malaria, asymptomatic parasitemia, or healthy controls. SDF-1 levels were higher in children with acute malaria compared with healthy controls. Together, these results uncover a potentially novel role for endothelial progenitor cell mobilization in the pathophysiology of cerebral malaria.

  15. Arterial ageing: from endothelial dysfunction to vascular calcification.

    Science.gov (United States)

    Tesauro, M; Mauriello, A; Rovella, V; Annicchiarico-Petruzzelli, M; Cardillo, C; Melino, G; Di Daniele, N

    2017-05-01

    Complex structural and functional changes occur in the arterial system with advancing age. The aged artery is characterized by changes in microRNA expression patterns, autophagy, smooth muscle cell migration and proliferation, and arterial calcification with progressively increased mechanical vessel rigidity and stiffness. With age the vascular smooth muscle cells modify their phenotype from contractile to 'synthetic' determining the development of intimal thickening as early as the second decade of life as an adaptive response to forces acting on the arterial wall. The increased permeability observed in intimal thickening could represent the substrate on which low-level atherosclerotic stimuli can promote the development of advanced atherosclerotic lesions. In elderly patients the atherosclerotic plaques tend to be larger with increased vascular stenosis. In these plaques there is a progressive accumulation of both lipids and collagen and a decrease of inflammation. Similarly the plaques from elderly patients show more calcification as compared with those from younger patients. The coronary artery calcium score is a well-established marker of adverse cardiovascular outcomes. The presence of diffuse calcification in a severely stenotic segment probably induces changes in mechanical properties and shear stress of the arterial wall favouring the rupture of a vulnerable lesion in a less stenotic adjacent segment. Oxidative stress and inflammation appear to be the two primary pathological mechanisms of ageing-related endothelial dysfunction even in the absence of clinical disease. Arterial ageing is no longer considered an inexorable process. Only a better understanding of the link between ageing and vascular dysfunction can lead to significant advances in both preventative and therapeutic treatments with the aim that in the future vascular ageing may be halted or even reversed. © 2017 The Association for the Publication of the Journal of Internal Medicine.

  16. Histamine Induces Vascular Hyperpermeability by Increasing Blood Flow and Endothelial Barrier Disruption In Vivo.

    Science.gov (United States)

    Ashina, Kohei; Tsubosaka, Yoshiki; Nakamura, Tatsuro; Omori, Keisuke; Kobayashi, Koji; Hori, Masatoshi; Ozaki, Hiroshi; Murata, Takahisa

    2015-01-01

    Histamine is a mediator of allergic inflammation released mainly from mast cells. Although histamine strongly increases vascular permeability, its precise mechanism under in vivo situation remains unknown. We here attempted to reveal how histamine induces vascular hyperpermeability focusing on the key regulators of vascular permeability, blood flow and endothelial barrier. Degranulation of mast cells by antigen-stimulation or histamine treatment induced vascular hyperpermeability and tissue swelling in mouse ears. These were abolished by histamine H1 receptor antagonism. Intravital imaging showed that histamine dilated vasculature, increased blood flow, while it induced hyperpermeability in venula. Whole-mount staining showed that histamine disrupted endothelial barrier formation of venula indicated by changes in vascular endothelial cadherin (VE-cadherin) localization at endothelial cell junction. Inhibition of nitric oxide synthesis (NOS) by L-NAME or vasoconstriction by phenylephrine strongly inhibited the histamine-induced blood flow increase and hyperpermeability without changing the VE-cadherin localization. In vitro, measurements of trans-endothelial electrical resistance of human dermal microvascular endothelial cells (HDMECs) showed that histamine disrupted endothelial barrier. Inhibition of protein kinase C (PKC) or Rho-associated protein kinase (ROCK), NOS attenuated the histamine-induced barrier disruption. These observations suggested that histamine increases vascular permeability mainly by nitric oxide (NO)-dependent vascular dilation and subsequent blood flow increase and maybe partially by PKC/ROCK/NO-dependent endothelial barrier disruption.

  17. VASCULAR ENDOTHELIAL GROWTH FACTOR IN HEALTH AND DISEASE: A REVIEW

    Directory of Open Access Journals (Sweden)

    Niranjan Gopal

    2016-10-01

    Full Text Available BACKGROUND Vascular Endothelial Growth Factor (VEGF has been implicated as a key molecule, which regulates physiological angiogenesis. VEGF exerts its molecular actions through Receptor Tyrosine Kinases (RTKs VEGFR-1 and VEGFR-2, differ in signaling properties. VEGF plays a vital role in embryogenesis, growth and reproduction. VEGF as a mediator of pathological angiogenesis is associated with proliferation and micrometastasis of various tumours, ocular disorders involving neovascularisation, pre-eclampsia, etc. The pathogenesis of micro and macrovascular complications of diabetes mellitus and the role of VEGF is being studied extensively. Currently, several pharmacological interventions based on VEGF inhibitors and receptor antagonists have been tried to combat the pathological angiogenesis in a wide gamut of disorders. This review attempts to put together important properties, mechanism of action and the role of VEGF in common diseased states. CONCLUSION Effects of VEGF are widespread and have been implicated in several disease states. Therapeutic modalities targeting VEGF have been tried with success in recent years.

  18. Vascular endothelial growth factor blocking agents in retinal vein occlusion

    Directory of Open Access Journals (Sweden)

    Chris Canning

    2008-01-01

    Full Text Available This paper summarises the current status of the use of vascular endothelial growth factor (VEGF blocking agents in retinal vein occlusion. There have been no randomised controlled trials comparing this treatment with the current standard treatment (largely laser so the lower grade evidence of single treatment case series and anecdotal reports are discussed. VEGF blockers are good at reducing macular oedema in the short term, do improve visual acuity in many cases, and do not seem to adversely affect the long term revascularisation that is necessary to overcome the vein occlusion. VEGF blocking agents are not used in isolation in this condition - they will remain an adjunct to systemic and other local treatments. The literature was reviewed in online searches of Embase and Ovid and the papers quoted are a representative sample of a larger body of publications.

  19. Soluble vascular endothelial growth factor in various blood transfusion components

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen; Werther, K; Mynster, T;

    1999-01-01

    BACKGROUND: Blood transfusion may reduce survival after curative surgery for solid tumors. This may be related to extracellular content of cancer growth factors present in transfusion components. Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis in solid tumors....... The potential content of VEGF in various blood components for transfusion was evaluated. STUDY DESIGN AND METHODS: Soluble VEGF (sVEGF, isotype 165) was determined by an enzyme-linked immunosorbent assay (EIA) in serum and plasma samples and in lysed cells from healthy volunteers. Subsequently, total content...... of platelet-derived soluble plasminogen activator inhibitor type 1 (sPAI-1) was determined by an EIA in the same samples. Finally, the extracellular accumulation of sVEGF was determined in nonfiltered WB and SAGM blood during storage for 35 days and in BCP pools during storage for 7 days. RESULTS...

  20. Soluble vascular endothelial growth factor in various blood transfusion components

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen; Werther, K; Mynster, T

    1999-01-01

    BACKGROUND: Blood transfusion may reduce survival after curative surgery for solid tumors. This may be related to extracellular content of cancer growth factors present in transfusion components. Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis in solid tumors....... The potential content of VEGF in various blood components for transfusion was evaluated. STUDY DESIGN AND METHODS: Soluble VEGF (sVEGF, isotype 165) was determined by an enzyme-linked immunosorbent assay (EIA) in serum and plasma samples and in lysed cells from healthy volunteers. Subsequently, total content......-reduced PRP. The sVEGF accumulated significantly in WB, SAGM blood, and BCP pools, depending on the storage time. CONCLUSION: The sVEGF (isotype 165) appears to be present in various blood transfusion components, depending on storage time....

  1. Levamisole induced apoptosis in cultured vascular endothelial cells

    Science.gov (United States)

    Artwohl, Michaela; Hölzenbein, Thomas; Wagner, Ludwig; Freudenthaler, Angelika; Waldhäusl, Werner; Baumgartner-Parzer, Sabina M

    2000-01-01

    To better understand the anticancer activity of Levamisole (LMS), which serves as an adjuvant in colon cancer therapy in combination with 5-Fluorouracil, this study analyses LMS' ability to induce apoptosis and growth arrest in cultured human micro- and macrovascular endothelial cells (ECs) and fibroblasts. Cells exposed (24 h) to Levamisole (range: 0.5–2 mmol l−1) alone or in combination with antioxidants (10 mmol l−1 glutathione or 5 mmol l−1 N-Acetylcysteine or 0.1 mmol l−1 Tocopherol) were evaluated for apoptosis (3H-thymidine assays, in situ staining), mRNA/protein expression (Northern/Western blot), and proliferation (3H-thymidine incorporation). Levamisole dose-dependently increased apoptosis in ECs to 230% (HUVECs-human umbilical vein ECs), 525% (adult human venous ECs) and 600% (human uterine microvascular ECs) but not in fibroblasts compared to control cells (set as 100%). Levamisole increased in ECs integrin-dependent matrix adhesion, inhibited proliferation (−70%), reduced expression of survival factors such as clusterin (−30%), endothelin-1 (−43%), bcl-2 (−34%), endothelial NO-synthase (−32%) and pRb (Retinoblastoma protein: −89%), and increased that of growth arrest/death signals such as p21 (+73%) and bak (+50%). LMS (2 mmol l−1)-induced apoptosis was inhibited by glutathione (−50%) and N-Acetylcysteine (−36%), which also counteracted reduction by Levamisole of pRb expression, suggesting reactive oxygen species and pRb play a role in these processes. The ability of LMS to selectively induce apoptosis and growth arrest in endothelial cells potentially hints at vascular targeting to contribute to Levamisole's anticancer activity. PMID:11139434

  2. Endothelial Microparticle-Derived Reactive Oxygen Species: Role in Endothelial Signaling and Vascular Function

    Directory of Open Access Journals (Sweden)

    Dylan Burger

    2016-01-01

    Full Text Available Endothelial microparticles are effectors of endothelial damage; however mechanisms involved are unclear. We examined the effects of eMPs on cultured endothelial cells (ECs and isolated vessels and investigated the role of eMP-derived reactive oxygen species (ROS and redox signaling in these processes. eMPs were isolated from EC media and their ability to directly produce ROS was assessed by lucigenin and liquid chromatography. Nicotinamide adenine dinucleotide phosphate oxidase (Nox subunits were probed by Western blot. ECs were treated with eMPs and effects on kinase signaling, superoxide anion (O2∙- generation, and nitric oxide (NO production were examined. Acetylcholine-mediated vasorelaxation was assessed by myography in eMP-treated mesenteric arteries. eMPs contained Nox1, Nox2, Nox4, p47phox, p67phox, and p22phox and they produced ROS which was inhibited by the Nox inhibitor, apocynin. eMPs increased phosphorylation of ERK1/2 and Src, increased O2∙- production, and decreased A23187-induced NO production in ECs. Pretreatment of eMPs with apocynin diminished eMP-mediated effects on ROS and NO production but had no effect on eMP-mediated kinase activation or impairment in vasorelaxation. Our findings identify a novel mechanism whereby eMP-derived ROS contributes to MP bioactivity. These interactions may be important in conditions associated with vascular injury and increased eMP formation.

  3. Effect of combined VEGF165/ SDF-1 gene therapy on vascular remodeling and blood perfusion in cerebral ischemia.

    Science.gov (United States)

    Hu, Guo-Jie; Feng, Yu-Gong; Lu, Wen-Peng; Li, Huan-Ting; Xie, Hong-Wei; Li, Shi-Fang

    2016-12-16

    OBJECTIVE Therapeutic neovascularization is a promising strategy for treating patients after an ischemic stroke; however, single-factor therapy has limitations. Stromal cell-derived factor 1 (SDF-1) and vascular endothelial growth factor (VEGF) proteins synergistically promote angiogenesis. In this study, the authors assessed the effect of combined gene therapy with VEGF165 and SDF-1 in a rat model of cerebral infarction. METHODS An adenoviral vector expressing VEGF165 and SDF-1 connected via an internal ribosome entry site was constructed (Ad- VEGF165-SDF-1). A rat model of middle cerebral artery occlusion (MCAO) was established; either Ad- VEGF165-SDF-1 or control adenovirus Ad- LacZ was stereotactically microinjected into the lateral ventricle of 80 rats 24 hours after MCAO. Coexpression and distribution of VEGF165 and SDF-1 were examined by reverse-transcription polymerase chain reaction, Western blotting, and immunofluorescence. The neurological severity score of each rat was measured on Days 3, 7, 14, 21, and 28 after MCAO. Angiogenesis and vascular remodeling were evaluated via bromodeoxyuridine and CD34 immunofluorescence labeling. Relative cerebral infarction volumes were determined by T2-weighted MRI and triphenyltetrazolium chloride staining. Cerebral blood flow, relative cerebral blood volume, and relative mean transmit time were assessed using perfusion-weighted MRI. RESULTS The Ad- VEGF165-SDF-1 vector mediated coexpression of VEGF165 and SDF-1 in multiple sites around the ischemic core, including the cortex, corpus striatum, and hippocampal granular layer. Coexpression of VEGF165 and SDF-1 improved neural function, reduced cerebral infarction volume, increased microvascular density and promoted angiogenesis in the ischemic penumbra, and improved cerebral blood flow and perfusion. CONCLUSIONS Combined VEGF165 and SDF-1 gene therapy represents a potential strategy for improving vascular remodeling and recovery of neural function after cerebral

  4. Endothelial-mural cell signaling in vascular development and angiogenesis.

    Science.gov (United States)

    Gaengel, Konstantin; Genové, Guillem; Armulik, Annika; Betsholtz, Christer

    2009-05-01

    Mural cells are essential components of blood vessels and are necessary for normal development, homeostasis, and organ function. Alterations in mural cell density or the stable attachment of mural cells to the endothelium is associated with several human diseases such as diabetic retinopathy, venous malformation, and hereditary stroke. In addition mural cells are implicated in regulating tumor growth and have thus been suggested as potential antiangiogenic targets in tumor therapy. In recent years our knowledge of mural cell function and endothelial-mural cell signaling has increased dramatically, and we now begin to understand the mechanistic basis of the key signaling pathways involved. This is mainly thanks to sophisticated in vivo experiments using a broad repertoire of genetic technologies. In this review, we summarize the five currently best understood signaling pathways implicated in mural cell biology. We discuss PDGFB/PDGFRbeta- dependent pericyte recruitment, as well as the role of angiopoietins and Tie receptors in vascular maturation. In addition, we highlight the effects of sphingosine-1-phosphate signaling on adherens junction assembly and vascular stability, as well as the role of TGF-beta-signaling in mural cell differentiation. We further reflect recent data suggesting an important function for Notch3 signaling in mural cell maturation.

  5. Rhubarb Antagonizes Matrix Metalloproteinase-9-induced Vascular Endothelial Permeability

    Institute of Scientific and Technical Information of China (English)

    Yun-Liang Cui; Sheng Zhang; Zhao-Tao Tian; Zhao-Fen Lin; De-Chang Chen

    2016-01-01

    Background:Intact endothelial structure and function are critical for maintaining microcirculatory homeostasis.Dysfunction of the latter is an underlying cause of various organ pathologies.In a previous study,we showed that rhubarb,a traditional Chinese medicine,protected intestinal mucosal microvascular endothelial cells in rats with metastasizing septicemia.In this study,we investigated the effects and mechanisms of rhubarb on matrix metalloproteinase-9 (MMP9)-induced vascular endothelial (VE) permeability.Methods:Rhubarb monomers were extracted and purified by a series of chromatography approaches.The identity of these monomers was analyzed by hydrogen-1 nuclear magnetic resonance (NMR),carbon-13 NMR,and distortionless enhancement by polarization transfer magnetic resonance spectroscopy.We established a human umbilical vein endothelial cell (HUVEC) monolayer on a Transwell insert.We measured the HUVEC permeability,proliferation,and the secretion of VE-cadherin into culture medium using fluorescein isothiocyanate-dextran assay,3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay,and enzyme-linked immunosorbent assay,respectively,in response to treatment with MMP9 and/or rhubarb monomers.Results:A total of 21 rhubarb monomers were extracted and identified.MMP9 significantly increased the permeability of the HUVEC monolayer,which was significantly reduced by five individual rhubarb monomer (emodin,3,8-dihydroxy-1-methyl-anthraquinone-2-carboxylic acid,1-O-caffeoyl-2-(4-hydroxyl-O-cinnamoyl)-β-D-glucose,daucosterol linoleate,and rhein) or a combination of all five monomers (1 μmol/L for each monomer).Mechanistically,the five-monomer mixture at 1 μmol/L promoted HUVEC proliferation.In addition,MMP9 stimulated the secretion of VE-cadherin into the culture medium,which was significantly inhibited by the five-monomer mixture.Conclusions:The rhubarb mixture of emodin,3,8-dihydroxy-1-methyl-anthraquinone-2-carboxylic acid,1-O-caffeoyl-2-(4-hydroxyl

  6. Anesthetic Propofol Overdose Causes Vascular Hyperpermeability by Reducing Endothelial Glycocalyx and ATP Production

    Science.gov (United States)

    Lin, Ming-Chung; Lin, Chiou-Feng; Li, Chien-Feng; Sun, Ding-Ping; Wang, Li-Yun; Hsing, Chung-Hsi

    2015-01-01

    Prolonged treatment with a large dose of propofol may cause diffuse cellular cytotoxicity; however, the detailed underlying mechanism remains unclear, particularly in vascular endothelial cells. Previous studies showed that a propofol overdose induces endothelial injury and vascular barrier dysfunction. Regarding the important role of endothelial glycocalyx on the maintenance of vascular barrier integrity, we therefore hypothesized that a propofol overdose-induced endothelial barrier dysfunction is caused by impaired endothelial glycocalyx. In vivo, we intraperitoneally injected ICR mice with overdosed propofol, and the results showed that a propofol overdose significantly induced systemic vascular hyperpermeability and reduced the expression of endothelial glycocalyx, syndecan-1, syndecan-4, perlecan mRNA and heparan sulfate (HS) in the vessels of multiple organs. In vitro, a propofol overdose reduced the expression of syndecan-1, syndecan-4, perlecan, glypican-1 mRNA and HS and induced significant decreases in the nicotinamide adenine dinucleotide (NAD+)/NADH ratio and ATP concentrations in human microvascular endothelial cells (HMEC-1). Oligomycin treatment also induced significant decreases in the NAD+/NADH ratio, in ATP concentrations and in syndecan-4, perlecan and glypican-1 mRNA expression in HMEC-1 cells. These results demonstrate that a propofol overdose induces a partially ATP-dependent reduction of endothelial glycocalyx expression and consequently leads to vascular hyperpermeability due to the loss of endothelial barrier functions. PMID:26023717

  7. Procyanidins Mitigate Osteoarthritis Pathogenesis by, at Least in Part, Suppressing Vascular Endothelial Growth Factor Signaling

    Science.gov (United States)

    Wang, Angela; Leong, Daniel J.; He, Zhiyong; Xu, Lin; Liu, Lidi; Kim, Sun Jin; Hirsh, David M.; Hardin, John A.; Cobelli, Neil J.; Sun, Hui B.

    2016-01-01

    Procyanidins are a family of plant metabolites that have been suggested to mitigate osteoarthritis pathogenesis in mice. However, the underlying mechanism is largely unknown. This study aimed to determine whether procyanidins mitigate traumatic injury-induced osteoarthritis (OA) disease progression, and whether procyanidins exert a chondroprotective effect by, at least in part, suppressing vascular endothelial growth factor signaling. Procyanidins (extracts from pine bark), orally administered to mice subjected to surgery for destabilization of the medial meniscus, significantly slowed OA disease progression. Real-time polymerase chain reaction revealed that procyanidin treatment reduced expression of vascular endothelial growth factor and effectors in OA pathogenesis that are regulated by vascular endothelial growth factor. Procyanidin-suppressed vascular endothelial growth factor expression was correlated with reduced phosphorylation of vascular endothelial growth factor receptor 2 in human OA primary chondrocytes. Moreover, components of procyanidins, procyanidin B2 and procyanidin B3 exerted effects similar to those of total procyanidins in mitigating the OA-related gene expression profile in the primary culture of human OA chondrocytes in the presence of vascular endothelial growth factor. Together, these findings suggest procyanidins mitigate OA pathogenesis, which is mediated, at least in part, by suppressing vascular endothelial growth factor signaling. PMID:27941690

  8. Value of measuring serum vascular endothelial growth factor levels in diagnosing acute ischemic stroke.

    Science.gov (United States)

    Dassan, Pooja; Keir, Geoffrey; Jäger, Hans Rolf; Brown, Martin M

    2012-08-01

    It has previously been reported that serum levels of vascular endothelial growth factor are raised after acute ischemic stroke compared to healthy controls. The aim of this prospective study was to ascertain whether serum vascular endothelial growth factor measurements could be used to distinguish between acute ischemic stroke and common stroke mimics in the emergency room. Blood samples were taken on arrival to hospital and daily for six-days, in 44 patients with suspected ischemic stroke (29 acute infarcts and 15 stroke mimics), arriving within 24 h of symptom onset. Vascular endothelial growth factor levels were measured by enzyme-linked immunoassay. The neurological deficit was recorded daily using the National Institute of Health Stroke Scale. Evaluation of infarct volumes was based on diffusion-weighted magnetic resonance imaging. Serum vascular endothelial growth factor levels were significantly raised in acute ischemic stroke patients on the day of symptom onset and at all other time points, compared to healthy controls (P acute ischemic stroke on admission to hospital were only 69% and 73%, respectively. Vascular endothelial growth factor levels were also elevated in four out of 15 stroke mimics, including three patients presenting with postictal paresis. Vascular endothelial growth factor has limited clinical utility in the diagnosis of acute ischemic stroke in the emergency room because levels are also raised in common stroke mimics. Further studies are required to establish the mechanism of vascular endothelial growth factor elevation in postictal paresis. © 2011 The Authors. International Journal of Stroke © 2011 World Stroke Organization.

  9. Procyanidins Mitigate Osteoarthritis Pathogenesis by, at Least in Part, Suppressing Vascular Endothelial Growth Factor Signaling

    Directory of Open Access Journals (Sweden)

    Angela Wang

    2016-12-01

    Full Text Available Procyanidins are a family of plant metabolites that have been suggested to mitigate osteoarthritis pathogenesis in mice. However, the underlying mechanism is largely unknown. This study aimed to determine whether procyanidins mitigate traumatic injury-induced osteoarthritis (OA disease progression, and whether procyanidins exert a chondroprotective effect by, at least in part, suppressing vascular endothelial growth factor signaling. Procyanidins (extracts from pine bark, orally administered to mice subjected to surgery for destabilization of the medial meniscus, significantly slowed OA disease progression. Real-time polymerase chain reaction revealed that procyanidin treatment reduced expression of vascular endothelial growth factor and effectors in OA pathogenesis that are regulated by vascular endothelial growth factor. Procyanidin-suppressed vascular endothelial growth factor expression was correlated with reduced phosphorylation of vascular endothelial growth factor receptor 2 in human OA primary chondrocytes. Moreover, components of procyanidins, procyanidin B2 and procyanidin B3 exerted effects similar to those of total procyanidins in mitigating the OA-related gene expression profile in the primary culture of human OA chondrocytes in the presence of vascular endothelial growth factor. Together, these findings suggest procyanidins mitigate OA pathogenesis, which is mediated, at least in part, by suppressing vascular endothelial growth factor signaling.

  10. Cerebral Endothelial Function Determined by Cerebrovascular Reactivity to L-Arginine

    Directory of Open Access Journals (Sweden)

    Janja Pretnar-Oblak

    2014-01-01

    Full Text Available Endothelium forms the inner cellular lining of blood vessels and plays an important role in many physiological functions including the control of vasomotor tone. Cerebral endothelium is probably one of the most specific types but until recently it was impossible to determine its function. In this review, the role of cerebrovascular reactivity to L-arginine (CVR-L-Arg for assessment of cerebral endothelial function is discussed. L-Arginine induces vasodilatation through enhanced production of nitric oxide (NO in the cerebral endothelium. Transcranial Doppler sonography is used for evaluation of cerebral blood flow changes. The method is noninvasive, inexpensive, and enables reproducible measurements. CVR-L-Arg has been compared to flow-mediated dilatation as a gold standard for systemic endothelial function and intima-media thickness as a marker for morphological changes. However, it seems to show specific cerebral endothelial function. So far CVR-L-Arg has been used to study cerebral endothelial function in many pathological conditions such as stroke, migraine, etc. In addition CVR-L-Arg has also proven its usefulness in order to show potential improvement after pharmacological interventions. In conclusion CVR-L-Arg is a promising noninvasive research method that could provide means for evaluation of cerebral endothelial function in physiological and pathological conditions.

  11. Isolation of Endothelial Cells and Vascular Smooth Muscle Cells from Internal Mammary Artery Tissue

    Science.gov (United States)

    Moss, Stephanie C.; Bates, Michael; Parrino, Patrick E.; Woods, T. Cooper

    2007-01-01

    Analyses of vascular smooth muscle cell and endothelial cell function through tissue culture techniques are often employed to investigate the underlying mechanisms regulating cardiovascular disease. As diseases such as diabetes mellitus and chronic kidney disease increase a patient's risk of cardiovascular disease, the development of methods for examining the effects of these diseases on vascular smooth muscle cells and endothelial cells is needed. Commercial sources of endothelial cells and vascular smooth muscle cells generally provide minimal donor information and are in limited supply. This study was designed to determine if vascular smooth muscle cells and endothelial cells could be isolated from human internal mammary arteries obtained from donors undergoing coronary artery bypass graft surgery. As coronary artery bypass graft surgery is a commonly performed procedure, this method would provide a new source for these cells that when combined with the donor's medical history will greatly enhance our studies of the effects of complicating diseases on vascular biology. Internal mammary artery tissue was obtained from patients undergoing coronary artery bypass graft surgery. Through a simple method employing two separate tissue digestions, vascular smooth muscle cells and endothelial cells were isolated and characterized. The isolated vascular smooth muscle cells and endothelial cells exhibited the expected morphology and were able to be passaged for further analysis. The vascular smooth muscle cells exhibited positive staining for α-smooth muscle actin and the endothelial cells exhibited positive staining for CD31. The overall purity of the isolations was > 95%. This method allows for the isolation of endothelial cells and vascular smooth muscle cells from internal mammary arteries, providing a new tool for investigations into the interplay of vascular diseases and complicating diseases such as diabetes and kidney disease. PMID:21603530

  12. Vascular inward rectifier K+ channels as external K+ sensors in the control of cerebral blood flow.

    Science.gov (United States)

    Longden, Thomas A; Nelson, Mark T

    2015-04-01

    For decades it has been known that external K(+) ions are rapid and potent vasodilators that increase CBF. Recent studies have implicated the local release of K(+) from astrocytic endfeet-which encase the entirety of the parenchymal vasculature-in the dynamic regulation of local CBF during NVC. It has been proposed that the activation of KIR channels in the vascular wall by external K(+) is a central component of these hyperemic responses; however, a number of significant gaps in our knowledge remain. Here, we explore the concept that vascular KIR channels are the major extracellular K(+) sensors in the control of CBF. We propose that K(+) is an ideal mediator of NVC, and discuss KIR channels as effectors that produce rapid hyperpolarization and robust vasodilation of cerebral arterioles. We provide evidence that KIR channels, of the KIR 2 subtype in particular, are present in both the endothelial and SM cells of parenchymal arterioles and propose that this dual positioning of KIR 2 channels increases the robustness of the vasodilation to external K(+), enables the endothelium to be actively engaged in NVC, and permits electrical signaling through the endothelial syncytium to promote upstream vasodilation to modulate CBF.

  13. Effects of Estrogen Level on the Function of Vascular Endothelial Cells and Expression of Vascular Cell Adhesion Molecule - 1φ

    Institute of Scientific and Technical Information of China (English)

    WU Saizhu(吴赛珠); LIU Jiangguo(刘建国); TAN Jiayu(谭家余); ZHoU Kexiang(周可祥); Gorge D Webb; WEI Heming(隗和明); GUO Zhiguang(郭志刚)

    2002-01-01

    Objectives To ob- serve the effect of different estrogen levels on the se- cretory function of vascular endothelial cells of female rats, and study the effect of modulation of estrogen level on the expression of vascular cell adhesion molecule - 1 and the concentration of estrogen receptorin vascular endothelial cells. Methods Radioim-munology was used to measure the serum concentrationof endothelin and PGI2, and copper-cadmium re-duction was employed to measure the serum content ofnitrogen monoxide. Radioligand binding and flowcy-tometry were used to measure the expression of estrogenreceptor and vascular cell adhesion molecule (VCAM-1 ) of vascular endothelial cells respectively. Re-sults 1. The serum concentration of nitric oxide andPGI2 decreased when the ovaries of female rats wereremoved. In ovariectomized rats, given estrogen, theconcentration rose ( P < 0.05), but the plasma con-centration of endothelin was adverse to it. 2. Theconcentration of estrogen receptor of vascular endothe-lial cells decreased remarkably when the ovaries of fe-male rats were removed. When given estrogen, it in-creased. 3. The percent of expressed VCAM - 1 in-creased siguificantly after interleukin- lβoperated onthe cells, but 17 - βestradiol at 3 × 10-8 ~ 10-6 mol/lall decreased the percent. Conclusions Estrogenlevel can influence the secretion of nitrogen monoxide,PGI2 and endothlin of vascular endothelial cells, andalso influence the concentration of estrogen receptor ofvascular endothelial cells. 17 -β Estradiol at 3 × 10-8~ 10-6 M can decrease the elevation of VCAM - 1 ofvascular endothelial cells induced by interleukin - 1 β.

  14. Assessment of vascular and endothelial dysfunction in nutritional studies.

    Science.gov (United States)

    Ray, S; Miglio, C; Eden, T; Del Rio, D

    2014-09-01

    Vascular and endothelial dysfunction (VED) is emerging as a potential set of early markers of cardiovascular disease risk and tests for its measurement have been widely used in clinical research. The aim of this viewpoint is to describe and discuss the current usage of these measures in well-designed nutritional trials, using the potential relationship between fruit juice intake and VED as example. A search was conducted using the NHS evidence portal including studies published in English between January 1980 and October 2013. Only 10 suitable studies were selected, which investigated the effect of fruit juice intake on VED, among which 4 interventions used flow-mediated dilatation, 2 arterial stiffness, 2 a combination of arterial stiffness and flow-mediated dilatation, 2 carotid intimal media thickness and 1 iontophoresis with laser Doppler. Despite minimal effects reported on classical CVD markers, such as lipids, 8 out of the 10 identified studies reported an effect on endothelial function following juice consumption, indicating that VED tests can be effectively used in human dietary interventions to identify relationships between bioactive compounds from fruit and CVD risk. However, paucity of available data, scarcity of compound bioavailability and metabolism information, strong heterogeneity among experimental methodologies and a number of limitations to study designs, still limit the interpretation of the results obtained through these measures. Future, well-designed studies with greater attention to consider use of VED measures are needed to strengthen the utility of VED tests in nutrition research such as those investigating the impact of polyphenol-rich juices and CVD risk.

  15. Cheiradone: a vascular endothelial cell growth factor receptor antagonist

    Directory of Open Access Journals (Sweden)

    Ahmed Nessar

    2008-01-01

    Full Text Available Abstract Background Angiogenesis, the growth of new blood vessels from the pre-existing vasculature is associated with physiological (for example wound healing and pathological conditions (tumour development. Vascular endothelial growth factor (VEGF, fibroblast growth factor-2 (FGF-2 and epidermal growth factor (EGF are the major angiogenic regulators. We have identified a natural product (cheiradone isolated from a Euphorbia species which inhibited in vivo and in vitro VEGF- stimulated angiogenesis but had no effect on FGF-2 or EGF activity. Two primary cultures, bovine aortic and human dermal endothelial cells were used in in vitro (proliferation, wound healing, invasion in Matrigel and tube formation and in vivo (the chick chorioallantoic membrane models of angiogenesis in the presence of growth factors and cheiradone. In all cases, the concentration of cheiradone which caused 50% inhibition (IC50 was determined. The effect of cheiradone on the binding of growth factors to their receptors was also investigated. Results Cheiradone inhibited all stages of VEGF-induced angiogenesis with IC50 values in the range 5.20–7.50 μM but did not inhibit FGF-2 or EGF-induced angiogenesis. It also inhibited VEGF binding to VEGF receptor-1 and 2 with IC50 values of 2.9 and 0.61 μM respectively. Conclusion Cheiradone inhibited VEGF-induced angiogenesis by binding to VEGF receptors -1 and -2 and may be a useful investigative tool to study the specific contribution of VEGF to angiogenesis and may have therapeutic potential.

  16. Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons

    OpenAIRE

    Guo, Shuzhen; Kim, Woo Jean; Lok, Josephine; Lee, Sun-Ryung; Besancon, Elaine; Luo, Bing-Hao; Stins, Monique F.; Wang, Xiaoying; Dedhar, Shoukat; Lo, Eng H.

    2008-01-01

    The neurovascular unit is an emerging concept that emphasizes homeostatic interactions between endothelium and cerebral parenchyma. Here, we show that cerebral endothelium are not just inert tubes for delivering blood, but they also secrete trophic factors that can be directly neuroprotective. Conditioned media from cerebral endothelial cells broadly protects neurons against oxygen-glucose deprivation, oxidative damage, endoplasmic reticulum stress, hypoxia, and amyloid neurotoxicity. This ph...

  17. Salvianolic acid B improves vascular endothelial function in diabetic rats with blood glucose fluctuations via suppression of endothelial cell apoptosis.

    Science.gov (United States)

    Ren, Younan; Tao, Shanjun; Zheng, Shuguo; Zhao, Mengqiu; Zhu, Yuanmei; Yang, Jieren; Wu, Yuanjie

    2016-11-15

    Vascular endothelial cell injury is an initial event in atherosclerosis. Salvianolic acid B (Sal B), a main bioactive component in the root of Salvia miltiorrhiza, has vascular protective effect in diabetes, but the underlying mechanisms remain unclear. The present study investigated the effect of Sal B on vascular endothelial function in diabetic rats with blood glucose fluctuations and the possible mechanisms implicated. The results showed that diabetic rats developed marked endothelial dysfunction as exhibited by impaired acetylcholine induced vasodilation. Supplementation with Sal B resulted in an evident improvement of endothelial function. Phosphorylation (Ser 1177) of endothelial nitric oxide synthase (eNOS) was significantly restored in Sal B treated diabetic rats, accompanied by an evident recovery of NO metabolites. Sal B effectively reduced vascular endothelial cell apoptosis, with Bcl-2 protein up-regulated and Bax protein down-regulated markedly. Treatment with Sal B led to an evident amelioration of oxidative stress in diabetic rats as manifested by enhanced antioxidant capacity and decreased contents of malondialdehyde in aortas. Protein levels of NOX2 and NOX4, two main isoforms of NADPH oxidase known as the major source of reactive oxygen species in the vasculature, were markedly decreased in Sal B treated groups. In addition, treatment with Sal B led to an evident decrease of serum lipids. Taken together, this study indicates that Sal B is capable of improving endothelial function in diabetic rats with blood glucose fluctuations, of which the underlying mechanisms might be related to suppression of endothelial cell apoptosis and stimulation of eNOS phosphorylation (Ser 1177).

  18. Post-transcriptional gene regulation by RNA-binding proteins in vascular endothelial dysfunction.

    Science.gov (United States)

    Xin, HongBo; Deng, KeYu; Fu, MinGui

    2014-08-01

    Endothelial cell dysfunction is a term which implies the dysregulation of normal endothelial cell functions, including impairment of the barrier functions, control of vascular tone, disturbance of proliferative and migratory capacity of endothelial cells, as well as control of leukocyte trafficking. Endothelial dysfunction is an early step in vascular inflammatory diseases such as atherosclerosis, diabetic vascular complications, sepsis-induced or severe virus infection-induced organ injuries. The expressions of inflammatory cytokines and vascular adhesion molecules induced by various stimuli, such as modified lipids, smoking, advanced glycation end products and bacteria toxin, significantly contribute to the development of endothelial dysfunction. The transcriptional regulation of inflammatory cytokines and vascular adhesion molecules has been well-studied. However, the regulation of those gene expressions at post-transcriptional level is emerging. RNA-binding proteins have emerged as critical regulators of gene expression acting predominantly at the post-transcriptional level in microRNA-dependent or independent manners. This review summarizes the latest insights into the roles of RNA-binding proteins in controlling vascular endothelial cell functions and their contribution to the pathogenesis of vascular inflammatory diseases.

  19. A Case Report of Ischemic Stroke in a Patient with Metastatic Gastric Cancer Secondary to Treatment with the Vascular Endothelial Growth Factor Receptor-2 Inhibitor Ramucirumab

    Directory of Open Access Journals (Sweden)

    Michael E. Christiansen

    2016-06-01

    Full Text Available Ramucirumab is an antiangiogenesis agent targeting the vascular endothelial growth factor receptor-2 (VEGFR-2, approved to treat advanced gastric and colon cancer. In clinical trials, it was shown to cause a small increase in arterial thromboembolism compared to placebo, including cerebral and myocardial ischemia, which was not statistically significant. Detailed case reports are lacking and we here present one of the first case reports of stroke secondary to ramucirumab-induced in situ thrombosis.

  20. Vascular endothelial-cadherin downregulation as a feature of endothelial transdifferentiation in monocrotaline-induced pulmonary hypertension.

    Science.gov (United States)

    Nikitopoulou, Ioanna; Orfanos, Stylianos E; Kotanidou, Anastasia; Maltabe, Violetta; Manitsopoulos, Nikolaos; Karras, Panagiotis; Kouklis, Panos; Armaganidis, Apostolos; Maniatis, Nikolaos A

    2016-08-01

    Increased pulmonary vascular resistance in pulmonary hypertension (PH) is caused by vasoconstriction and obstruction of small pulmonary arteries by proliferating vascular cells. In analogy to cancer, subsets of proliferating cells may be derived from endothelial cells transitioning into a mesenchymal phenotype. To understand phenotypic shifts transpiring within endothelial cells in PH, we injected rats with alkaloid monocrotaline to induce PH and measured lung tissue levels of endothelial-specific protein and critical differentiation marker vascular endothelial (VE)-cadherin. VE-cadherin expression by immonoblotting declined significantly 24 h and 15 days postinjection to rebound to baseline at 30 days. There was a concomitant increase in transcriptional repressors Snail and Slug, along with a reduction in VE-cadherin mRNA. Mesenchymal markers α-smooth muscle actin and vimentin were upregulated by immunohistochemistry and immunoblotting, and α-smooth muscle actin was colocalized with endothelial marker platelet endothelial cell adhesion molecule-1 by confocal microscopy. Apoptosis was limited in this model, especially in the 24-h time point. In addition, monocrotaline resulted in activation of protein kinase B/Akt, endothelial nitric oxide synthase (eNOS), nuclear factor (NF)-κB, and increased lung tissue nitrotyrosine staining. To understand the etiological relationship between nitrosative stress and VE-cadherin suppression, we incubated cultured rat lung endothelial cells with endothelin-1, a vasoconstrictor and pro-proliferative agent in pulmonary arterial hypertension. This resulted in activation of eNOS, NF-κB, and Akt, in addition to induction of Snail, downregulation of VE-cadherin, and synthesis of vimentin. These effects were blocked by eNOS inhibitor N(ω)-nitro-l-arginine methyl ester. We propose that transcriptional repression of VE-cadherin by nitrosative stress is involved in endothelial-mesenchymal transdifferentiation in experimental PH.

  1. Regulation Effect of Vascular Endothelial Growth Factor on Human Fetal Choroid Vascularization

    Institute of Scientific and Technical Information of China (English)

    JinsongZhao; YiWang; 等

    2002-01-01

    Purpose:To investigate the spatial and temporal regulation effect of vascular endothelial growth factor(VEGF) on human fetal choroids vascularization.Methods:The eyeballs of 54 human fetuses from the 9th week to the 40th week due to accidental abortion were studied by immunohistochemically stainin for the expression of VEGF and proliferation cell nuclear antigen (PCNA).Results: (1)The distribution of VEGF expression in the retinal pigment epithelium (RPE) decreased with the incrase of age,the peak of which was between the 9th and 14th week.(2)PCNA immunoreactivity was localized within choriocapillaris endothelium .The expression level decreased alone with fetus age.In this period the choriocapillaris endothelium kept proliferation,differentiation,canalization and remodeled to form the choroids vessels(3)Statistically significant correlations were shown between the expression of VEGF in the PRE and that of PCNA in choriocapillaris endothelium(r=0.933,P<0.01).Couclusin:VEGF expression in PRE was positively involved in modulating human fetal choroids vascularization .Eye Science 2000;16:11-14.

  2. Regulation Effect of Vascular Endothelial Growth Factor on Human Fetal Choroid Vascularization

    Institute of Scientific and Technical Information of China (English)

    Jinsong Zhao; Yue Song; Yi Wang; Xiaoguang Zhang

    2000-01-01

    Purpose: To investigate the spatial and temporal regulation effect of vascular endothelial growth factor(VEGF) on human fetal choroid vascularization. Methods: The eyeballs of 54 human fetuses from the 9th week to the 40th week due to accidental abortion were studied by immunohistochemically staining for the expression of VEGF and proliferation cell nuclear antigen (PCNA). Results: (1) The distribution of VEGF expression in the retinal pigment epithelium (RPE) decreased with the increase of age, the peak of which was between the 9th and 14th week. (2) PCNA immunoreactivity was localized within choriocapillaris endothelium. The expression level decreased alone with fetus age. In this period the choriocapillaris endothelium kept proliferation, differentiation, canalization and remodelled to form the choroid vessels. (3)Statistically significant correlations were shown between the expression of VEGF in the PRE and that of PCNA in choriocapillaris endothelium(r =0. 933, P < 0. 01). Conclusion: VEGF expression in RPE was positively involved in modulating human fetal choroid vascularization. Eye Science 2000; 16:11 ~ 14.

  3. Expression of Vascular Endothelial Growth Factor-C and Vascular Endothelial Growth Factor Receptor-3 in Ovarian Epithelial Tumors

    Institute of Scientific and Technical Information of China (English)

    FU Xiao-yan; DING Ming-xing; ZHANG Ning; LIN Xing-qiu; LI Ji-cheng

    2007-01-01

    Objective: To explore the role of vascular endothelial growth factor-C (VEGF-C) in the process of angiogenesis, lymphangiogenesis and lymphatic metastasis in epithelial ovarian tumors. Methods: In situ hybridization and immunohistochemical staining for VEGF-C were performed in 30 epithelial ovarian carcinomas, 9 borderline tumors and 26 benign tumors. Endothelial cells were immunostained with anti-VEGFR-3 pAb and anti-CD31 mAb, and VEGFR-3 positive vessels and microvessel density (MVD) were assessed by image analysis. Results: VEGF-C mRNA and protein expression were detected in cytoplasm of carcinoma cells. VEGF-C mRNA and protein expression in ovarian epithelial carcinomas were significantly higher than those in borderline tumors and benign tumors (P<0.05 or P<0.01). In ovarian epithelial carcinomas, VEGF-C protein expression, VEGFR-3 positive vessels and MVD were significantly higher in the cases of clinical stage Ⅲ-Ⅳ and with lymph node metastasis than those of clinical stage Ⅰ-Ⅱ and without lymph node metastasis respectively (P<0.05 or P<0.01). VEGFR-3 positive vessels and MVD were significantly higher in VEGF-C protein positive tumors than negative tumors (P<0.05). VEGFR-3 positive vessels was significantly correlated with MVD(P<0.01). Conclusion: VEGF-C might play a role in lymphatic metastasis via lymphangiogenesis and angiogenesis in epithelial ovarian tumors, and VBEGF-C could be used as a biologic marker of metastasis in ovarian epithelial tumors.

  4. Viscoelastic properties of vascular endothelial cells exposed to uniaxial stretch

    Science.gov (United States)

    Osterday, Kathryn; Chew, Thomas; Loury, Phillip; Haga, Jason; Del Alamo, Juan C.; Chien, Shu

    2011-11-01

    Vascular endothelial cells (VECs) line the interior of blood vessels and regulate a variety of functions in the cardiovascular system. It is widely accepted that VECs will remodel themselves in response to mechanical stimuli, but few studies have analyzed the mechanical properties of these cells under stretch. We hypothesize that uniaxial stretch will cause an anisotropic realignment of actin filaments, and a change in the viscoelastic properties of the cell. To test this hypothesis, VECs were grown on a thin, transparent membrane mounted on a microscope. The membrane was stretched, consequently stretching the cells. Time-lapse sequences of the cells were taken every hour with a time resolution of 10 Hz. The random trajectories of intracellular endogenous particles were tracked using in-house algorithms. These trajectories were analyzed using a novel particle tracking microrheology formulation that takes into account the anisotropy of the cytoplasm of VECs. Supported by NSF CBET-1055697 CAREER Award (JCA) and NIH grants BRP HL064382 (SC), 1R01 HL080518 (SC).

  5. Vascular endothelial growth factor enhances macrophage clearance of apoptotic cells

    Science.gov (United States)

    Dalal, Samay; Horstmann, Sarah A.; Richens, Tiffany R.; Tanaka, Takeshi; Doe, Jenna M.; Boe, Darren M.; Voelkel, Norbert F.; Taraseviciene-Stewart, Laimute; Janssen, William J.; Lee, Chun G.; Elias, Jack A.; Bratton, Donna; Tuder, Rubin M.; Henson, Peter M.; Vandivier, R. William

    2012-01-01

    Efficient clearance of apoptotic cells from the lung by alveolar macrophages is important for the maintenance of tissue structure and function. Lung tissue from humans with emphysema contains increased numbers of apoptotic cells and decreased levels of vascular endothelial growth factor (VEGF). Mice treated with VEGF receptor inhibitors have increased numbers of apoptotic cells and develop emphysema. We hypothesized that VEGF regulates apoptotic cell clearance by alveolar macrophages (AM) via its interaction with VEGF receptor 1 (VEGF R1). Our data show that the uptake of apoptotic cells by murine AMs and human monocyte-derived macrophages is inhibited by depletion of VEGF and that VEGF activates Rac1. Antibody blockade or pharmacological inhibition of VEGF R1 activity also decreased apoptotic cell uptake ex vivo. Conversely, overexpression of VEGF significantly enhanced apoptotic cell uptake by AMs in vivo. These results indicate that VEGF serves a positive regulatory role via its interaction with VEGF R1 to activate Rac1 and enhance AM apoptotic cell clearance. PMID:22307908

  6. Analysis of vascular endothelial dysfunction genes and related pathways in obesity through systematic bioinformatics.

    Science.gov (United States)

    Zhang, Hui; Wang, Jing; Sun, Ling; Xu, Qiuqin; Hou, Miao; Ding, Yueyue; Huang, Jie; Chen, Ye; Cao, Lei; Zhang, Jianmin; Qian, Weiguo; Lv, Haitao

    2015-01-01

    Obesity has become an increasingly serious health problem and popular research topic. It is associated with many diseases, especially cardiovascular disease (CVD)-related endothelial dysfunction. This study analyzed genes related to endothelial dysfunction and obesity and then summarized their most significant signaling pathways. Genes related to vascular endothelial dysfunction and obesity were extracted from a PubMed database, and analyzed by STRING, DAVID, and Gene-Go Meta-Core software. 142 genes associated with obesity were found to play a role in endothelial dysfunction in PubMed. A significant pathway (Angiotensin system maturation in protein folding and maturation) associated with obesity and endothelial dysfunction was explored. The genes and the pathway explored may play an important role in obesity. Further studies about preventing vascular endothelial dysfunction obesity should be conducted through targeting these loci and pathways.

  7. Relationship between vascular endothelial function and pulse wave velocity in prehypertension

    Institute of Scientific and Technical Information of China (English)

    杨娉婷

    2014-01-01

    Objective To investigate the association between vascular endothelial function and arteriosclerosis in prehypertensive,hypertensive and healthy subjects.Methods 810 consecutive subjects were divided into three groups:hypertension group,prehypertension group and control group.Brachial-ankle pulse wave velocity(ba PWV)and flow-mediated brachial artery dilation(FMD)were used to evaluate the artery vascular stiffness and endothelial function respectively.Results Prehypertension

  8. The effects of TSH on human vascular endothelial cells and smooth muscle cells

    Institute of Scientific and Technical Information of China (English)

    田利民

    2014-01-01

    Objective To study the effect of thyroid-stimulating hormone(TSH)on human vascular endothelial cells and smooth muscle cells and to explore the roles of TSH in the development of atherosclerosis.Methods Human vascular endothelial cells and smooth muscle cells were cultured in vitro.MTT method was used to assay the effect of TSH on cell viability.Real-time PCR was used

  9. Red light, green light: Signals that control endothelial cell proliferation during embryonic vascular development

    Science.gov (United States)

    The proper regulation of endothelial cell proliferation is critical for vascular development in the embryo. VEGF-A and bFGF, which are important in the induction of mesodermal progenitors to form a capillary plexus, are also key mitogenic signals. Disruption in VEGF-A or bFGF decreases endothelial c...

  10. Preservation of endothelial integrity and function in experimental vascular anastomosis with non-penetrating clips

    NARCIS (Netherlands)

    Zeebregts, C; van den Dungen, J; Buikema, H; Tiebosch, A; van der Want, J; van Schilfgaarde, R

    2001-01-01

    Background: Vascular repair with sutures is associated with disruption of the endothelial lining and subsequent thrombus formation on the intraluminal lesions. This experimental study was designed to determine whether the use of non-penetrating clips improved endothelial preservation. Methods: In te

  11. RAPID ENDOTHELIALIZATION OF VASCULAR PROSTHESES BY SEEDING AUTOLOGOUS VENOUS TISSUE FRAGMENTS

    NARCIS (Netherlands)

    NOISHIKI, Y; YAMANE, Y; TOMIZAWA, Y; OKOSHI, T; SATOH, S; WILDEVUUR, CRH; SUZUKI, K

    1992-01-01

    A method was developed to obtain rapid endothelialization of a fabric vascular prosthesis by seeding autologous venous tissue fragments into its wall. In an animal study, complete endothelialization was observed in the entire inner surface of the prosthesis within 2 weeks after implantation. A piece

  12. Microfluidic technology in vascular research : the endothelial response to shear stress

    NARCIS (Netherlands)

    van der Meer, Andries Dirk

    2010-01-01

    Vascular endothelial cells form the inner lining of all blood vessels. These cells are highly responsive to the shear stress that is caused by blood flowing over their surface. In this thesis, several aspects of the endothelial response to shear stress are studied. The experiments focus on signal

  13. Placental growth factor and vascular endothelial growth factor receptor-2 in human lung development.

    Science.gov (United States)

    Janér, Joakim; Andersson, Sture; Haglund, Caj; Karikoski, Riitta; Lassus, Patrik

    2008-08-01

    We examined the pulmonary expression of 2 proangiogenic factors, namely, placental growth factor and vascular endothelial growth factor receptor-2, during lung development and acute and chronic lung injury in newborn infants. Six groups were included in an immunohistochemical study of placental growth factor and vascular endothelial growth factor receptor-2, that is, 9 fetuses, 4 preterm and 8 term infants without lung injury who died soon after birth, 5 preterm infants with respiratory distress syndrome of 10 days, and 6 with bronchopulmonary dysplasia. Placental growth factor concentrations in tracheal aspirate fluid were measured in 70 samples from 20 preterm infants during the first postnatal week. In immunohistochemical analyses, placental growth factor staining was seen in bronchial epithelium and macrophages in all groups. Distal airway epithelium positivity was observed mostly in fetuses and in preterm infants who died soon after birth. Vascular endothelial growth factor receptor-2 staining was seen in vascular endothelium in all groups and also in lymphatic endothelium in fetuses. Vascular endothelial growth factor receptor-2 staining in arterial endothelium was associated with higher and staining in venous endothelium with lower gestational age. In capillaries, less vascular endothelial growth factor receptor-2 staining was seen in bronchopulmonary dysplasia. The mean placental growth factor protein concentration in tracheal aspirate fluid during the first postnatal week was 0.64 +/- 0.42 pg/mL per IgA-secretory component unit. Concentrations during the first postnatal week were stable. Lower placental growth factor concentrations correlated with chorioamnionitis and lactosyl ceramide positivity. The vascular endothelial growth factor receptor-2 staining pattern seems to reflect ongoing differentiation and activity of different endothelia. Lower vascular endothelial growth factor receptor-2 expression in capillary endothelium in bronchopulmonary dysplasia

  14. Vascular endothelial growth factor-dependent angiogenesis and dynamic vascular plasticity in the sensory circumventricular organs of adult mouse brain.

    Science.gov (United States)

    Morita, Shoko; Furube, Eriko; Mannari, Tetsuya; Okuda, Hiroaki; Tatsumi, Kouko; Wanaka, Akio; Miyata, Seiji

    2015-03-01

    The sensory circumventricular organs (CVOs), which comprise the organum vasculosum of the lamina terminalis (OVLT), the subfornical organ (SFO) and the area postrema (AP), lack a typical blood-brain barrier (BBB) and monitor directly blood-derived information to regulate body fluid homeostasis, inflammation, feeding and vomiting. Until now, almost nothing has been documented about vascular features of the sensory CVOs except fenestration of vascular endothelial cells. We therefore examine whether continuous angiogenesis occurs in the sensory CVOs of adult mouse. The angiogenesis-inducing factor vascular endothelial growth factor-A (VEGF-A) and the VEGF-A-regulating transcription factor hypoxia-inducible factor-1α were highly expressed in neurons of the OVLT and SFO and in both neurons and astrocytes of the AP. Expression of the pericyte-regulating factor platelet-derived growth factor B was high in astrocytes of the sensory CVOs. Immunohistochemistry of bromodeoxyuridine and Ki-67, a nuclear protein that is associated with cellular proliferation, revealed active proliferation of endothelial cells. Moreover, immunohistochemistry of caspase-3 and the basement membrane marker laminin showed the presence of apoptosis and sprouting of endothelial cells, respectively. Treatment with the VEGF receptor-associated tyrosine kinase inhibitor AZD2171 significantly reduced proliferation and filopodia sprouting of endothelial cells, as well as the area and diameter of microvessels. The mitotic inhibitor cytosine-b-D-arabinofuranoside reduced proliferation of endothelial cells and the vascular permeability of blood-derived low-molecular-weight molecules without changing vascular area and microvessel diameter. Thus, our data indicate that continuous angiogenesis is dependent on VEGF signaling and responsible for the dynamic plasticity of vascular structure and permeability.

  15. Vascular endothelial growth factor-B promotes in vivo angiogenesis.

    Science.gov (United States)

    Silvestre, Jean-Sébastien; Tamarat, Radia; Ebrahimian, Teni G; Le-Roux, Aude; Clergue, Michel; Emmanuel, Florence; Duriez, Micheline; Schwartz, Bertrand; Branellec, Didier; Lévy, Bernard I

    2003-07-25

    Vascular endothelial growth factors (VEGFs) and their receptors have emerged as central regulators of the angiogenic process. However, involvement of VEGF-B, one of these factors, in angiogenesis remains obscure. Mice received subcutaneous injection of Matrigel alone or Matrigel with human recombinant protein rhVEGF-B167 or with rhVEGF-A165. After 14 days, cell ingrowth in the Matrigel plug was increased by 2.0- and 2.5-fold in rhVEGF-B167-treated and rhVEGF-A165-treated mice, respectively (P<0.01), in association with a raise in phospho-Akt/Akt (1.8-fold, P<0.01) and endothelial NO synthase (eNOS) (1.80- and 1.60-fold, respectively; P<0.05) protein levels measured by Western blot. VEGF-B-induced cell ingrowth was impaired by treatment with NOS inhibitor (NG-nitro-l-arginine methyl ester; L-NAME, 10 mg/kg per day). Treatment with neutralizing antibody directed against the VEGF-B receptor VEGF-R1 (anti-VEGFR1, 10 microg) completely abrogated VEGF-B-related effects. Proangiogenic effect of VEGF-B was confirmed in a mouse model of surgically induced hindlimb ischemia. Plasmids containing human form of VEGF-A (phVEGF-A165) or VEGF-B (phVEGF-B167 or phVEGF-B186) were administered by in vivo electrotransfer. Angiographic score at day 28 showed significant improvement in ischemic/nonischemic leg ratio by 1.4- and 1.5-fold in mice treated with phVEGF-B167 and phVEGF-B186, respectively (P<0.05). Laser Doppler perfusion data also evidenced a 1.5-fold increase in phVEGF-B167-treated and phVEGF-B186-treated mice (P<0.05). Such an effect was associated with an upregulation of phospho-Akt/Akt and eNOS protein levels in the ischemic legs and was hampered by treatment with anti-VEGFR1. This study demonstrates for the first time that VEGF-B, in part through its receptor VEGF-R1, promotes angiogenesis in association with an activation of Akt and eNOS-related pathways.

  16. Eicosanoid signaling and vascular dysfunction: methylmercury-induced phospholipase D activation in vascular endothelial cells.

    Science.gov (United States)

    Sherwani, Shariq I; Pabon, Sheila; Patel, Rishi B; Sayyid, Muzzammil M; Hagele, Thomas; Kotha, Sainath R; Magalang, Ulysses J; Maddipati, Krishna R; Parinandi, Narasimham L

    2013-11-01

    Mercury, especially methylmercury (MeHg), is implicated in the etiology of cardiovascular diseases. Earlier, we have reported that MeHg induces phospholipase D (PLD) activation through oxidative stress and thiol-redox alteration. Hence, we investigated the mechanism of the MeHg-induced PLD activation through the upstream regulation by phospholipase A2 (PLA2) and lipid oxygenases such as cyclooxygenase (COX) and lipoxygenase (LOX) in the bovine pulmonary artery endothelial cells (BPAECs). Our results showed that MeHg significantly activated both PLA2 (release of [(3)H]arachidonic acid, AA) and PLD (formation of [(32)P]phosphatidylbutanol) in BPAECs in dose- (0-10 μM) and time-dependent (0-60 min) fashion. The cPLA2-specific inhibitor, arachidonyl trifluoromethyl ketone (AACOCF3), significantly attenuated the MeHg-induced [(3)H]AA release in ECs. MeHg-induced PLD activation was also inhibited by AACOCF3 and the COX- and LOX-specific inhibitors. MeHg also induced the formation of COX- and LOX-catalyzed eicosanoids in ECs. MeHg-induced cytotoxicity (based on lactate dehydrogenase release) was protected by PLA2-, COX-, and LOX-specific inhibitors and 1-butanol, the PLD-generated PA quencher. For the first time, our studies showed that MeHg activated PLD in vascular ECs through the upstream action of cPLA2 and the COX- and LOX-generated eicosanoids. These results offered insights into the mechanism(s) of the MeHg-mediated vascular endothelial cell lipid signaling as an underlying cause of mercury-induced cardiovascular diseases.

  17. Vascular endothelial growth factor and not cyclooxygenase 2 promotes endothelial cell viability in the pancreatic tumor microenvironment.

    LENUS (Irish Health Repository)

    Toomey, Desmond P

    2010-07-01

    Cyclooxygenase 2 (COX-2) and vascular endothelial growth factor (VEGF), often coexpressed in cancer, are associated with poor prognosis. However, results from pancreatic cancer trials of their inhibitors were disappointing. This study delineated the role of COX-2 and nonsteroidal anti-inflammatory drugs in angiogenesis and VEGF regulation.

  18. VASCULAR ENDOTHELIAL GROWTH FACTORS IN HEART TRANSPLANT REJECTIONS

    Directory of Open Access Journals (Sweden)

    O. P. Shevchenko

    2015-01-01

    Full Text Available Aim: to determine the clinical significance of vascular endothelial growth factors VEGF-A, VEGF-D, PlGF-1 to assess the risk of cardiovascular complications in heart recipients. Materials and methods. 103 patients, aged 16 to 73 years, 85 males and 18 females. 65 recipients (47 men and 18 women had dilated cardiomyopathy, 38 – coronary heart disease (CHD. The concentration of VEGF-A, VEGF-D, PlGF-1 was measured using xMAP technology with sets of reagents Simplex ProcartaPlex™. Results. After HTx the level of VEGF-A significantly decreased, p = 0.001. There were no correlations between the levels of VEGF-A, VEGF-D and PlGF-1 with age, gender and diagnosis. After HTx VEGF-A level was higher in recipients with ACR than in those without it (p = 0.001. ACR frequency was significantly higher in patients with high VEGF-A level (≥316.5 pg/ml, RR = 5.8 ± 0.5, AUC = 0.779. After HTx PlGF-1 level was higher in recipients with ACR too (p = 0.039. ACR frequency was significantly higher in patients with high PlGF-1 level (≥5.33 pg/ml, RR = 1.8 ± 0.5, AUC = 0.65. There were no correlations between VEGF-D level with ACR and all three biomarkers with AMR. ACR frequency was significantly higher with both high VEGF-A and PlGF-1 levels (RR = 6.4. Conclusion. Serum levels of VEGF-A and PlGF-1 after HTx may be regarded as indicators of increased risk of ACR.

  19. Vascular endothelial growth factor (VEGF and prostate pathology

    Directory of Open Access Journals (Sweden)

    Francisco Botelho

    2010-08-01

    Full Text Available PURPOSE: Previous studies suggest that vascular endothelial growth factor (VEGF circulating levels might improve identification of patients with prostate cancer but results are conflicting. Our aim was to compare serum VEGF levels across different prostate pathologies (including benign prostatic hyperplasia, prostatitis, high grade prostate intraepithelial neoplasia and prostate cancer in patients at high risk of prostate cancer. MATERIALS AND METHODS: We consecutively enrolled 186 subjects with abnormal digital rectal examination and/or total PSA (tPSA = 2.5 ng/mL. Blood was collected before diagnostic ultrasound guided trans-rectal prostate biopsy, or any prostate oncology treatment, to measure PSA isoforms and VEGF. Unconditional logistic regression was used to compute age-, tPSA- and free/total PSA-adjusted odds ratios (OR and respective 95% confidence intervals (95% CI for the association between serum VEGF and different prostatic pathologies. RESULTS: Prostate biopsy main diagnoses were normal or benign prostatic hyperplasia (27.3%, prostatitis (16.6%, and prostatic cancer (55.0%. The median VEGF levels (ng/mL in these groups were 178.2, 261.3 and 266.4 (p = 0.029, respectively, but no significant differences were observed for benign vs. malignant pathologies (215.2 vs. 266.4, p = 0.551. No independent association was observed between VEGF (3rd vs. 1st third and prostate cancer, when compared to benign conditions (adjusted OR = 1.44; CI 95%: 0.64-3.26. CONCLUSIONS: In patients at high risk of prostate cancer, circulating VEGF levels have no clinical role in deciding which patients should be submitted to prostate biopsy. Prostatitis patients, often with higher PSA levels, also present high serum levels of VEGF, and their inclusion in control groups might explain the heterogeneous results in previous studies.

  20. Stem cell-derived vascular endothelial cells and their potential application in regenerative medicine

    Science.gov (United States)

    Although a 'vascular stem cell' population has not been identified or generated, vascular endothelial and mural cells (smooth muscle cells and pericytes) can be derived from currently known pluripotent stem cell sources, including human embryonic stem cells and induced pluripotent stem cells. We rev...

  1. Study on the biological characteristics of pancreatic cancer vascular endothelial cells

    Institute of Scientific and Technical Information of China (English)

    李雷

    2012-01-01

    Objective To explore the biological characteristics of pancreatic cancer vascular endothelial cells,including the aspects of morphology,species,genetics,vascular formation ability,and proliferation ability in vitro. Methods The human pancreatic cancer cells were inoculated in nude mice pancreas to get pancreatic cancer

  2. Value of cerebral perfusion and vascular reserve for the treatment of symptomatic intracranial arterial stenosis

    Institute of Scientific and Technical Information of China (English)

    Li'an Huang; Xuewen Song; Anding Xu

    2008-01-01

    BACKGROUND: It is crucial to understand cerebral perfusion and vascular reserve in stegnotic arterial blood-supply regions to treat ischemic cerebrovascular diseases. However, effects on symptomatic intracrani-al arterial stenosis (SICAS) need to be further studied in additional applications. OBJECTIVE: To evaluate and summarize the effects of cerebral perfusion and vascular reserve on the treatment of SICAS. RETRIEVAL STRATEGY: A computer-based online search of English language publications from January 2000 to July 2007 was conducted in PubMed to identify publications that addressed cerebral perfusion and vascular reserve of SICAS. Search key words were "intracranial stenosis, perfusion, brain reserve". Relevant data were also searched with the China Journal Net, using the same key words in Chinese from January 2000 to January 2007. In total, 101 articles were retrieved. Inclusion criteria: ① Articles describing the current status for the diagnosis and treatment of SICAS; ② Articles concerning research developments of cerebral perfusion and vascular reserve of SICAS. Exclusion criteria: duplicated articles. LITERATURE EVALUATION: This study included 21 articles of experimental studies and conference re-ports.DATA SYNTHESIS: When performing interventional surgery in SICAS patients, it is important to under-stand cerebral perfusion and vascular reserve in addition to knowing the clinical symptoms and degrees of arterial stenosis. In recent years, there are a growing number of reports on measurements of vascular reserve through the use of magnetic resonance perfusion imaging (MR-PWI). Investigations demonstrate cerebral perfusion and vascular reserve decrease in many SICAS patients. Many studies show that both improve after surgical intervention. CONCLUSION: Cerebral perfusion could provide direct evidence of whether ischemia has occurred in the brain. Because of lateral circulation and cerebral vascular reserve, intracranial vascular stenosis and/or decreased

  3. A novel mechanism of diabetic vascular endothelial dysfunction: Hypoadiponectinemia-induced NLRP3 inflammasome activation.

    Science.gov (United States)

    Zhang, Jinglong; Xia, Linying; Zhang, Fen; Zhu, Di; Xin, Chao; Wang, Helin; Zhang, Fuyang; Guo, Xian; Lee, Yan; Zhang, Ling; Wang, Shan; Guo, Xiong; Huang, Chong; Gao, Feng; Liu, Yi; Tao, Ling

    2017-02-12

    It has been well documented that hypoadiponectinemia is associated with impaired endothelium-dependent vasodilation. However, the exact molecular mechanism which mediates this process has not been fully described. The current study aimed to investigate the role of hypoadiponectinemia-induced NLRP3 inflammasome activation in diabetic vascular endothelial dysfunction and its molecular mechanism. Male adult adiponectin knockout mice and wild type mice were fed with a high fat diet to establish a type 2 diabetic mellitus model. In addition, human umbilical vein endothelial cells (HUVECs) were cultured and subjected to high glucose/high fat (HG/HF). The NLRP3 inflammasome activation was increased in type 2 diabetic mice and treatment of diabetic aortic segments with MCC950, a potent selective inhibitor of NLRP3 inflammasome ex vivo improved endothelial-dependent vasorelaxation. NLRP3 inflammasome activation and vascular endothelial injury were significantly increased in APN-KO mice compared with WT mice in diabetes and MCC950 decreased diabetic vascular endothelial dysfunction to comparable levels in APN-KO mice and WT mice. Adiponectin could decrease NLRP3 inflammasome activation and attenuate endothelial cell injury, which was abolished by NLRP3 inflammasome overexpression. Inhibition of peroxynitrite formation preferentially attenuated NLRP3 inflammasome activation in APN-KO diabetic mice. The current study demonstrated for the first time that hypoadiponectinemia-induced NLRP3 inflammasome activation was a novel mechanism of diabetic vascular endothelial dysfunction.

  4. Changes in the permeability of blood brain barrier and endothelial cell damage after cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Ke Liu; Jiansheng Li

    2006-01-01

    OBJECTIVE: To investigate the effect of endothelial cells on the permeability of blood brain barrier (BBB) after brain injury and its effect mechanism.DATA SOURCES: We searched for the articles of permeability of BBB and endothelial cell injury after brain ischemia, which were published between January 1982 and December 2005, with the key words of "cerebral ischemia damage,blood brain barrier ( BBB),permeability,effect of endothelial cell (EC) and its variation mechanism"in English.STUDY SELECTION: The materials were primarily selected. The articles related to the changes in the permeability of BBB and the effect of endothelial cells as well as the change mechanism after cerebral ischemia damage were chosen. Repetitive studies or review articles were excluded.DATA EXTRACTION: Totally 55 related articles were collected, and 35 were excluded due to repetitive or review articles, finally 20 articles were involved.DATA SYNTHESIS: The content or viewpoints of involved literatures were analyzed. Cerebral ischemia had damage for endothelial cells, such as the inflow of a lot of Ca2+, the production of nitrogen monoxide and oxygen free radical, and aggravated destruction of BBB. After acceptors of inflammatory mediators on cerebrovascular endothelial cell membrane, such as histamine, bradykinin , 5-hydroxytryptamine and so on are activated, endothelial cells shrink and the permeability of BBB increases. Its mechanism involves in the inflow of extracellular Ca2+and the release of intracellular Ca2+ in the cells. Glycocalyx molecule on the surface of endothelial cell, having structural polytropy, is the determinative factor of the permeability of BBB. VEGF, intensively increasing the vasopermeability and mainly effecting on postcapillary vein and veinlet, is the strongest known blood vessel permeation reagent. Its chronic overexpression in the brain can lead the destruction of BBB.CONCLUSION: The injury of endothelial cell participants in the pathological mechanism of BBB

  5. Arterioles in cerebral amyloid angiopathy and vascular dementia

    Institute of Scientific and Technical Information of China (English)

    ZHU Guang-ming; ZHANG Wei-wei; LIU Ying; LI Juan

    2009-01-01

    Background Small cerebrovascular lesions are one of the most important factors in cerebral amyloid angiopathy (CM) and vascular dementia (VaD). We analyzed the difference of arteriolar pathology between CM patients (CMs) and vascular dementia patients without CAA (VaDs).Methods Ten deceased CMs and twelve deceased VaDs were available for this study. Five deceased patients without known cerebrovascular diseases served as controls. These patients were all autopsy cases. All transversely cut arterioles in the gray matter and white matter with an external diameter equal to or larger than 30 μm and with a maximum of 300 μm were examined. The internal and external diameters of arterioles were measured. Results The external diameter of gray matter arterioles in the CAAs was significantly greater than in controls. In gray matter arterioles, the diameter of the lumen in VaDs was markedly smaller than in the CAAs, whereas there was no significant difference between CAAs and controls. CMs and VaDs may cause remarkable thickening of the arteriolar walls in either white matter or gray matter. The sclerotic index of arterioles in VaDs was significantly greater than in CAAs and controls. Conclusions Stenosis of arterioles occurred in both CM and VaD, but the tendency was greater in VaD. Arterioles of CM were also expanded in gray matter, which may be related to lobar hemorrhage. The loss and/or degeneration of vascular smooth muscle cells was predominant in CM, while the over-proliferation of vascular smooth muscle cells was greater in VaD.

  6. Heme oxygenase activity modulates vascular endothelial growth factor synthesis in vascular smooth muscle cells.

    Science.gov (United States)

    Dulak, Jozef; Józkowicz, Alicja; Foresti, Roberta; Kasza, Aneta; Frick, Matthias; Huk, Ihor; Green, Colin J; Pachinger, Otmar; Weidinger, Franz; Motterlini, Roberto

    2002-04-01

    Hypoxia, cytokines, and nitric oxide (NO) stimulate the generation of vascular endothelial growth factor (VEGF) and induce heme oxygenase-1 (HO-1) expression in vascular tissue. HO-1 degrades heme to carbon monoxide (CO), iron, and biliverdin, the latter being reduced to bilirubin by biliverdin reductase. In the present study, we investigated the role of HO-1 in the modulation of VEGF synthesis in rat vascular smooth muscle cells (VSMC). In VSMC stimulated with cytokines, inhibition of NO production significantly, but not completely, reduced VEGF release. In contrast, inhibition of HO activity by tin protoporphyrin IX (SnPPIX) totally prevented cytokine-induced increase in VEGF, despite an augmented synthesis of intracellular NO. Stimulation of HO-1 activity by hemin enhanced VEGF production; this effect was abrogated by blockade of the HO pathway. Similarly, VEGF synthesis induced by hypoxia was down-regulated by SnPPIX, but not by inhibitors of NO synthase. To elucidate further a direct involvement of HO-1 in the observed effects, we generated transfected cells that overexpressed the HO-1 gene. Notably, these cells synthesized significantly more VEGF protein than cells transfected with a control gene. Among the products of HO-1, biliverdin and bilirubin showed no effect, whereas iron ions inhibited VEGF synthesis. Exposure of cells to 1% CO resulted in a marked accumulation of VEGF (20-fold increase) over the basal level. Our data indicate that HO-1 activity influences the generation of VEGF in VSMC in both normoxic and hypoxic conditions. As CO and iron, respectively the inducer and the inhibitor of VEGF synthesis, are concomitantly produced during the degradation of heme, these data indicate that HO by-products may differentially modulate VEGF production.

  7. Damage of vascular endothelial barrier induced by explosive blast and its clinical significance

    Institute of Scientific and Technical Information of China (English)

    Jian-Min Wang; Jing Chen

    2016-01-01

    In recent years,injuries induced by explosive blast have got more and more attention owing to weapon development and frequent terrorist activities.Tear.bleeding and edema of tissues and organs are the main manifestations of blast shock wave damage.Vascular endothelial barrier is the main defense of tissues and organs' integrity.This article aims to discuss possible mechanisms of endothelial barrier damage induced by explosive blast and main manifestations of blood brain barrier,blood-air barrier,and intestinal vascular barrier impairments.In addition,the main regulatory factors of vascular permeability are also summarized so as to provide theoretical basis for prevention and cure of vascular endothelial barrier damage resulting from explosive blast.

  8. Structure and vascular function of MEKK3–cerebral cavernous malformations 2 complex

    Energy Technology Data Exchange (ETDEWEB)

    Fisher, Oriana S. [Yale Univ., New Haven, CT (United States); Deng, Hanqiang [Shanghai Jiao Tong Univ. School of Medicine (SJTU-SM), Shanghai (China); Liu, Dou [Yale Univ. School of Medicine, New Haven, CT (United States); Zhang, Ya [Yale Univ. School of Medicine, New Haven, CT (United States); Wei, Rong [Shanghai Jiao Tong Univ. School of Medicine (SJTU-SM), Shanghai (China); Deng, Yong [Yale Univ. School of Medicine, New Haven, CT (United States); Zhang, Fan [Yale Univ. School of Medicine, New Haven, CT (United States); Louvi, Angeliki [Yale Univ. School of Medicine, New Haven, CT (United States); Turk, Benjamin E. [Yale Univ., New Haven, CT (United States); Boggon, Titus J. [Yale Univ., New Haven, CT (United States); Su, Bing [Shanghai Jiao Tong Univ. School of Medicine (SJTU-SM), Shanghai (China)

    2015-08-03

    Cerebral cavernous malformations 2 (CCM2) loss is associated with the familial form of CCM disease. The protein kinase MEKK3 (MAP3K3) is essential for embryonic angiogenesis in mice and interacts physically with CCM2, but how this interaction is mediated and its relevance to cerebral vasculature are unknown. Here we report that Mekk3 plays an intrinsic role in embryonic vascular development. Inducible endothelial Mekk3 knockout in neonatal mice is lethal due to multiple intracranial haemorrhages and brain blood vessels leakage. We discover direct interaction between CCM2 harmonin homology domain (HHD) and the N terminus of MEKK3, and determine a 2.35 Å cocrystal structure. We find Mekk3 deficiency impairs neurovascular integrity, which is partially dependent on Rho–ROCK signalling, and that disruption of MEKK3:CCM2 interaction leads to similar neurovascular leakage. We conclude that CCM2:MEKK3-mediated regulation of Rho signalling is required for maintenance of neurovascular integrity, unravelling a mechanism by which CCM2 loss leads to disease.

  9. Vascular endothelial growth factors enhance the permeability of the mouse blood-brain barrier.

    Directory of Open Access Journals (Sweden)

    Shize Jiang

    Full Text Available The blood-brain barrier (BBB impedes entry of many drugs into the brain, limiting clinical efficacy. A safe and efficient method for reversibly increasing BBB permeability would greatly facilitate central nervous system (CNS drug delivery and expand the range of possible therapeutics to include water soluble compounds, proteins, nucleotides, and other large molecules. We examined the effect of vascular endothelial growth factor (VEGF on BBB permeability in Kunming (KM mice. Human VEGF165 was administered to treatment groups at two concentrations (1.6 or 3.0 µg/mouse, while controls received equal-volume saline. Changes in BBB permeability were measured by parenchymal accumulation of the contrast agent Gd-DTPA as assessed by 7 T magnetic resonance imaging (MRI. Mice were then injected with Evans blue, sacrificed 0.5 h later, and perfused transcardially. Brains were removed, fixed, and sectioned for histological study. Both VEGF groups exhibited a significantly greater signal intensity from the cerebral cortex and basal ganglia than controls (P<0.001. Evans blue fluorescence intensity was higher in the parenchyma and lower in the cerebrovasculature of VEGF-treated animals compared to controls. No significant brain edema was observed by diffusion weighted MRI (DWI or histological staining. Exogenous application of VEGF can increase the permeability of the BBB without causing brain edema. Pretreatment with VEGF may be a feasible method to facilitate drug delivery into the CNS.

  10. Insulin resistance in vascular endothelial cells promotes intestinal tumour formation

    DEFF Research Database (Denmark)

    Wang, X; Häring, M-F; Rathjen, Thomas

    2017-01-01

    in tumour endothelial cells produces an activated, proinflammatory state that promotes tumorigenesis. Improvement of endothelial dysfunction may reduce colorectal cancer risk in patients with obesity and type 2 diabetes.Oncogene advance online publication, 1 May 2017; doi:10.1038/onc.2017.107....

  11. Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons.

    Science.gov (United States)

    Guo, Shuzhen; Kim, Woo Jean; Lok, Josephine; Lee, Sun-Ryung; Besancon, Elaine; Luo, Bing-Hao; Stins, Monique F; Wang, Xiaoying; Dedhar, Shoukat; Lo, Eng H

    2008-05-27

    The neurovascular unit is an emerging concept that emphasizes homeostatic interactions between endothelium and cerebral parenchyma. Here, we show that cerebral endothelium are not just inert tubes for delivering blood, but they also secrete trophic factors that can be directly neuroprotective. Conditioned media from cerebral endothelial cells broadly protects neurons against oxygen-glucose deprivation, oxidative damage, endoplasmic reticulum stress, hypoxia, and amyloid neurotoxicity. This phenomenon is largely mediated by endothelial-produced brain-derived neurotrophic factor (BDNF) because filtering endothelial-conditioned media with TrkB-Fc eliminates the neuroprotective effect. Endothelial production of BDNF is sustained by beta-1 integrin and integrin-linked kinase (ILK) signaling. Noncytotoxic levels of oxidative stress disrupts ILK signaling and reduces endothelial levels of neuroprotective BDNF. These data suggest that cerebral endothelium provides a critical source of homeostatic support for neurons. Targeting these signals of matrix and trophic coupling between endothelium and neurons may provide new therapeutic opportunities for stroke and other CNS disorders.

  12. An Important Method in the Investigation of Vascular Pathologies: Endothelial Cell Culture

    Directory of Open Access Journals (Sweden)

    Yusufhan Yazır

    2012-12-01

    Full Text Available Endothelial cells line the interior surface of blood vessels and form an interface between circulating blood in the lumen and the rest of the vessel wall. Endothelial cells are involved in many aspects of vascular biology, including barrier function, vasoconstriction, coagulation and inflamation. The endothelial cells in different organs have different functions and surface phenotype. These cells express prostoglandin-I2, platelet activating factor, collagen, endothelin-1, laminin, fibronectin and growth factors including platelet derived growth factor, fibroblast growth factor. İn the cell culture, cells can be isolated, maintened and proliferate in the laboratory conditions. The techniques of the cell culture have allowed scientists to use the cells in vitro for experimental studies, such as the production of vaccine, antibody and enzime, drug research, cell-cell interactions. Human umbilical vein endothelial cell is a good source for endothelial cell, because it is cheaper, easy to find and has the basic features of the normal endothelial cells.

  13. Evidence that tumor necrosis factor-related apoptosis inducing ligand (TRAIL) inhibits angiogenesis by inducing vascular endothelial cell apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Pei-Lin, E-mail: pchen@dal.ca [Department of Pathology, Dalhousie University, Halifax, Nova Scotia (Canada); Easton, Alexander S., E-mail: alexander.easton@dal.ca [Department of Pathology, Dalhousie University, Halifax, Nova Scotia (Canada); Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia (Canada); Division of Neurosurgery, Department of Surgery, Dalhousie University, Halifax, Nova Scotia (Canada)

    2010-01-01

    Tumor necrosis factor (TNF) and its related ligands TNF-related apoptosis inducing ligand (TRAIL) and Fas ligand (FasL) play roles in the regulation of vascular responses, but their effect on the formation of new blood vessels (angiogenesis) is unclear. Therefore, we have examined the effects of these ligands on angiogenesis modeled with primary cultures of human umbilical vein endothelial cells (HUVEC). To examine angiogenesis in the context of the central nervous system, we have also modeled cerebral angiogenesis with the human brain endothelial cell line hCMEC/D3. Parameters studied were bromodeoxyuridine (BrdU) incorporation and cell number (MTT) assay (to assess endothelial proliferation), scratch assay (migration) and networks on Matrigel (tube formation). In our hands, neither TRAIL nor FasL (1, 10, and 100 ng/ml) had an effect on parameters of angiogenesis in the HUVEC model. In hCMEC/D3 cells by contrast, TRAIL inhibited all parameters (10-100 ng/ml, 24 h). This was due to apoptosis, since its action was blocked by the pan-caspase inhibitor zVADfmk (5 x 10{sup -5} mol/l) and TRAIL increased caspase-3 activity 1 h after application. However FasL (100 ng/ml) increased BrdU uptake without other effects. We conclude that TRAIL has different effects on in vitro angiogenesis depending on which model is used, but that FasL is generally ineffective when applied in vitro. The data suggest that TRAIL primarily influences angiogenesis by the induction of vascular endothelial apoptosis, leading to vessel regression.

  14. Hydrogen-Rich Medium Attenuated Lipopolysaccharide-Induced Monocyte-Endothelial Cell Adhesion and Vascular Endothelial Permeability via Rho-Associated Coiled-Coil Protein Kinase.

    Science.gov (United States)

    Xie, Keliang; Wang, Weina; Chen, Hongguang; Han, Huanzhi; Liu, Daquan; Wang, Guolin; Yu, Yonghao

    2015-07-01

    Sepsis is the leading cause of death in critically ill patients. In recent years, molecular hydrogen, as an effective free radical scavenger, has been shown a selective antioxidant and anti-inflammatory effect, and it is beneficial in the treatment of sepsis. Rho-associated coiled-coil protein kinase (ROCK) participates in junction between normal cells, and regulates vascular endothelial permeability. In this study, we used lipopolysaccharide to stimulate vascular endothelial cells and explored the effects of hydrogen-rich medium on the regulation of adhesion of monocytes to endothelial cells and vascular endothelial permeability. We found that hydrogen-rich medium could inhibit adhesion of monocytes to endothelial cells and decrease levels of adhesion molecules, whereas the levels of transepithelial/endothelial electrical resistance values and the expression of vascular endothelial cadherin were increased after hydrogen-rich medium treatment. Moreover, hydrogen-rich medium could lessen the expression of ROCK, as a similar effect of its inhibitor Y-27632. In addition, hydrogen-rich medium could also inhibit adhesion of polymorphonuclear neutrophils to endothelial cells. In conclusion, hydrogen-rich medium could regulate adhesion of monocytes/polymorphonuclear neutrophils to endothelial cells and vascular endothelial permeability, and this effect might be related to the decreased expression of ROCK protein.

  15. Endothelial heparan sulfate 6-O-sulfation levels regulate angiogenic responses of endothelial cells to fibroblast growth factor 2 and vascular endothelial growth factor

    NARCIS (Netherlands)

    Ferreras, C.; Rushton, G.; Cole, C.L.; Babur, Muhammad; Telfer, B.A.; Kuppevelt, A.H. van; Gardiner, J.M.; Williams, K.J.; Jayson, G.C.; Avizienyte, E.

    2012-01-01

    Fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor 165 (VEGF(165)) are potent pro-angiogenic growth factors that play a pivotal role in tumor angiogenesis. The activity of these growth factors is regulated by heparan sulfate (HS), which is essential for the formation of FGF2/FG

  16. Erythropoietin Attenuates Pulmonary Vascular Remodeling in Experimental Pulmonary Arterial Hypertension through Interplay between Endothelial Progenitor Cells and Heme Oxygenase

    NARCIS (Netherlands)

    van Loon, Rosa Laura E; Bartelds, Beatrijs; Wagener, Frank A D T G; Affara, Nada; Mohaupt, Saffloer; Wijnberg, Hans; Pennings, Sebastiaan W C; Takens, Janny; Berger, Rolf M F

    2015-01-01

    BACKGROUND: Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease with a high mortality, characterized by typical angio-proliferative lesions. Erythropoietin (EPO) attenuates pulmonary vascular remodeling in PAH. We postulated that EPO acts through mobilization of endothelial progeni

  17. Small GTP-Binding Protein Rac Is an Essential Mediator of Vascular Endothelial Growth Factor-Induced Endothelial Fenestrations and Vascular Permeability

    DEFF Research Database (Denmark)

    Eriksson, A.; Cao, R.; Tritsaris, K.

    2003-01-01

    ), endothelial nitric oxide synthase (eNOS), and extracellular regulated kinase (Erk1/2). We further found that phosphatidylinositol-3-OH kinase (PI3K) acted upstream of Rac and Akt-eNOS in VEGF/VEGFR-2 signaling. Conclusions- Our findings indicate that the small GTP-binding protein Rac is a key component...... and vascular permeability but only partially inhibited angiogenesis. Studies on endothelial cell cultures further revealed that VEGF stimulated phosphorylation of VEGF receptor-2 (VEGFR-2), leading to activation of Rac as well as increased phosphorylation of phospholipase C (PLC ), protein kinase B (Akt...

  18. Recent advances in understanding the roles of vascular endothelial cells in allergic inflammation.

    Science.gov (United States)

    Shoda, Tetsuo; Futamura, Kyoko; Orihara, Kanami; Emi-Sugie, Maiko; Saito, Hirohisa; Matsumoto, Kenji; Matsuda, Akio

    2016-01-01

    Allergic disorders commonly involve both chronic tissue inflammation and remodeling caused by immunological reactions to various antigens on tissue surfaces. Due to their anatomical location, vascular endothelial cells are the final responders to interact with various exogenous factors that come into contact with the epithelial surface, such as pathogen-associated molecular patterns (PAMPs) and antigens. Recent studies have shed light on the important roles of endothelial cells in the development and exacerbation of allergic disorders. For instance, endothelial cells have the greatest potential to produce several key molecules that are deeply involved in allergic inflammation, such as periostin and thymus and activation-regulated chemokine (TARC/CCL17). Additionally, endothelial cells were recently shown to be important functional targets for IL-33--an essential regulator of allergic inflammation. Notably, almost all endothelial cell responses and functions involved in allergic inflammation are not suppressed by corticosteroids. These corticosteroid-refractory endothelial cell responses and functions include TNF-α-associated angiogenesis, leukocyte adhesion, IL-33-mediated responses and periostin and TARC production. Therefore, these unique responses and functions of endothelial cells may be critically involved in the pathogenesis of various allergic disorders, especially their refractory processes. Here, we review recent studies, including ours, which have elucidated previously unknown pathophysiological roles of vascular endothelial cells in allergic inflammation and discuss the possibility of endothelium-targeted therapy for allergic disorders.

  19. Recent advances in understanding the roles of vascular endothelial cells in allergic inflammation

    Directory of Open Access Journals (Sweden)

    Tetsuo Shoda

    2016-01-01

    Full Text Available Allergic disorders commonly involve both chronic tissue inflammation and remodeling caused by immunological reactions to various antigens on tissue surfaces. Due to their anatomical location, vascular endothelial cells are the final responders to interact with various exogenous factors that come into contact with the epithelial surface, such as pathogen-associated molecular patterns (PAMPs and antigens. Recent studies have shed light on the important roles of endothelial cells in the development and exacerbation of allergic disorders. For instance, endothelial cells have the greatest potential to produce several key molecules that are deeply involved in allergic inflammation, such as periostin and thymus and activation-regulated chemokine (TARC/CCL17. Additionally, endothelial cells were recently shown to be important functional targets for IL-33—an essential regulator of allergic inflammation. Notably, almost all endothelial cell responses and functions involved in allergic inflammation are not suppressed by corticosteroids. These corticosteroid-refractory endothelial cell responses and functions include TNF-α-associated angiogenesis, leukocyte adhesion, IL-33-mediated responses and periostin and TARC production. Therefore, these unique responses and functions of endothelial cells may be critically involved in the pathogenesis of various allergic disorders, especially their refractory processes. Here, we review recent studies, including ours, which have elucidated previously unknown pathophysiological roles of vascular endothelial cells in allergic inflammation and discuss the possibility of endothelium-targeted therapy for allergic disorders.

  20. Beta-lactam antibiotic-mediated changes in platelet reactivity and vascular endothelial functions.

    Science.gov (United States)

    Togna, G I; Togna, A R; Caprino, L

    2001-05-01

    To evaluate vascular and platelet compatibility of intravenous administration of beta-lactam antibiotics, we assessed the effects of therapeutic concentrations of ceftriaxone, aztreonam, and ceftazidime on platelet reactivity to different agonists (sodium arachidonate, collagen and adenosine diphosphate) and on selected vascular endothelial functions (adenosine diphosphatase activity, prostacyclin production and t-PA release). Ceftriaxone and, to a lesser degree, aztreonam, enhanced platelet reactivity, evaluated as onset of platelet aggregating response, and increased thromboxane production to subthreshold concentrations of arachidonate. There was no modification in platelet reactivity after ceftazidime treatment. Ceftriaxone and ceftazidime, but not aztreonam, inhibited endothelial adenosine diphosphatase activity. Prostacyclin production and t-PA release were inhibited only by ceftriaxone at high concentrations. While it is difficult to establish which marker (platelet or endothelial functions) has more clinical reference in human vascular compatibility, it seems feasible to consider aztreonam the most compatible of the beta-lactams studied.

  1. Different contributions of clathrin- and caveolae-mediated endocytosis of vascular endothelial cadherin to lipopolysaccharide-induced vascular hyperpermeability.

    Science.gov (United States)

    Zhang, Ye; Zhang, Lianyang; Li, Yang; Sun, Shijin; Tan, Hao

    2014-01-01

    Vascular hyperpermeability induced by lipopolysaccharide (LPS) is a common pathogenic process in cases of severe trauma and sepsis. Vascular endothelial cadherin (VE-cad) is a key regulatory molecule involved in this process, although the detailed mechanism through which this molecule acts remains unclear. We assessed the role of clathrin-mediated and caveolae-mediated endocytosis of VE-cad in LPS-induced vascular hyperpermeability in the human vascular endothelial cell line CRL-2922 and determined that vascular permeability and VE-cad localization at the plasma membrane were negatively correlated after LPS treatment. Additionally, the loss of VE-cad at the plasma membrane was caused by both clathrin-mediated and caveolae-mediated endocytosis. Clathrin-mediated endocytosis was dominant early after LPS treatment, and caveolae-mediated endocytosis was dominant hours after LPS treatment. The caveolae-mediated endocytosis of VE-cad was activated through the LPS-Toll-like receptor 4 (TLR4)-Src signaling pathway. Structural changes in the actin cytoskeleton, specifically from polymerization to depolymerization, were important reasons for the switching of the VE-cad endocytosis pathway from clathrin-mediated to caveolae-mediated. Our findings suggest that clathrin-mediated and caveolae-mediated endocytosis of VE-cad contribute to LPS-induced vascular hyperpermeability, although they contribute via different mechanism. The predominant means of endocytosis depends on the time since LPS treatment.

  2. Leptin-induced transphosphorylation of vascular endothelial growth factor receptor increases Notch and stimulates endothelial cell angiogenic transformation.

    Science.gov (United States)

    Lanier, Viola; Gillespie, Corey; Leffers, Merle; Daley-Brown, Danielle; Milner, Joy; Lipsey, Crystal; Webb, Nia; Anderson, Leonard M; Newman, Gale; Waltenberger, Johannes; Gonzalez-Perez, Ruben Rene

    2016-10-01

    Leptin increases vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2), and Notch expression in cancer cells, and transphosphorylates VEGFR-2 in endothelial cells. However, the mechanisms involved in leptin's actions in endothelial cells are not completely known. Here we investigated whether a leptin-VEGFR-Notch axis is involved in these leptin's actions. To this end, human umbilical vein and porcine aortic endothelial cells (wild type and genetically modified to overexpress VEGFR-1 or -2) were cultured in the absence of VEGF and treated with leptin and inhibitors of Notch (gamma-secretase inhibitors: DAPT and S2188, and silencing RNA), VEGFR (kinase inhibitor: SU5416, and silencing RNA) and leptin receptor, OB-R (pegylated leptin peptide receptor antagonist 2: PEG-LPrA2). Interestingly, in the absence of VEGF, leptin induced the expression of several components of Notch signaling pathway in endothelial cells. Inhibition of VEGFR and Notch signaling significantly decreased leptin-induced S-phase progression, proliferation, and tube formation in endothelial cells. Moreover, leptin/OB-R induced transphosphorylation of VEGFR-1 and VEGFR-2 was essential for leptin's effects. These results unveil for the first time a novel mechanism by which leptin could induce angiogenic features via upregulation/trans-activation of VEGFR and downstream expression/activation of Notch in endothelial cells. Thus, high levels of leptin found in overweight and obese patients might lead to increased angiogenesis by activating VEGFR-Notch signaling crosstalk in endothelial cells. These observations might be highly relevant for obese patients with cancer, where leptin/VEGFR/Notch crosstalk could play an important role in cancer growth, and could be a new target for the control of tumor angiogenesis.

  3. Curcumin Attenuates Rapamycin-induced Cell Injury of Vascular Endothelial Cells.

    Science.gov (United States)

    Guo, Ning; Chen, Fangyuan; Zhou, Juan; Fang, Yuan; Li, Hongbing; Luo, Yongbai; Zhang, Yong

    2015-10-01

    Although drug-eluting stents (DES) effectively improve the clinical efficacy of percutaneous coronary intervention, a high risk of late stent thrombosis and in-stent restenosis also exists after DES implantation. Anti-smooth muscle proliferation drugs, such as rapamycin, coating stents, not only inhibit the growth of vascular smooth muscle cells but also inhibit vascular endothelial cells and delay the reendothelialization. Therefore, the development of an ideal agent that protects vascular endothelial cells from rapamycin-eluting stents is of great importance for the next generation of DES. In this study, we demonstrated that rapamycin significantly inhibited the growth of rat aortic endothelial cells in both dose- and time-dependent manner in vitro. Cell apoptosis was increased and migration was decreased by rapamycin treatments in rat aortic endothelial cells in vitro. Surprisingly, treatment with curcumin, an active ingredient of turmeric, significantly reversed these detrimental effects of rapamycin. Moreover, curcumin increased the expression of vascular nitric oxide synthases (eNOS), which was decreased by rapamycin. Furthermore, caveolin-1, the inhibitor of eNOS, was decreased by curcumin. Knockdown of eNOS by small interfering RNA significantly abrogated the protective effects of curcumin. Taken together, our results suggest that curcumin antagonizes the detrimental effect of rapamycin on aortic endothelial cells in vitro through upregulating eNOS. Therefore, curcumin is a promising combined agent for the rescue of DES-induced reendothelialization delay.

  4. Endothelial domes encapsulate adherent neutrophils and minimize increases in vascular permeability in paracellular and transcellular emigration.

    Directory of Open Access Journals (Sweden)

    Mia Phillipson

    Full Text Available Local edema, a cardinal sign of inflammation associates closely with neutrophil emigration. Neutrophil emigration has been described to occur primarily through endothelial junctions (paracellular and more rarely directly through endothelial cells (transcellular. Recently, we reported that unlike in wild-type (wt mice, Mac-1-/- (CD11b neutrophils predominantly emigrated transcellularly and was significantly delayed taking 20-30 min longer than the paracellular emigration (wt. In the present study we noted significant anatomical disruption of the endothelium and hypothesized that transcellular emigration would greatly increase vascular permeability. Surprisingly, despite profound disruption of the endothelial barrier as the neutrophils moved through the cells, the changes in vascular permeability during transcellular emigration (Mac-1-/- were not increased more than in wt mice. Instead increased vascular permeability completely tracked the number of emigrated cells and as such, permeability changes were delayed in Mac-1-/- mice. However, by 60 min neutrophils from both sets of mice were emigrating in large numbers. Electron-microscopy and spinning disk multichannel fluorescence confocal microscopy revealed endothelial docking structures that progressed to dome-like structures completely covering wt and Mac-1-/- neutrophils. These domes completely enveloped the emigrating neutrophils in both wt and Mac-1-/- mice making the mode of emigration underneath these structures extraneous to barrier function. In conclusion, predominantly paracellular versus predominantly transcellular emigration does not affect vascular barrier integrity as endothelial dome-like structures retain barrier function.

  5. Endothelial domes encapsulate adherent neutrophils and minimize increases in vascular permeability in paracellular and transcellular emigration.

    Science.gov (United States)

    Phillipson, Mia; Kaur, Jaswinder; Colarusso, Pina; Ballantyne, Christie M; Kubes, Paul

    2008-02-20

    Local edema, a cardinal sign of inflammation associates closely with neutrophil emigration. Neutrophil emigration has been described to occur primarily through endothelial junctions (paracellular) and more rarely directly through endothelial cells (transcellular). Recently, we reported that unlike in wild-type (wt) mice, Mac-1-/- (CD11b) neutrophils predominantly emigrated transcellularly and was significantly delayed taking 20-30 min longer than the paracellular emigration (wt). In the present study we noted significant anatomical disruption of the endothelium and hypothesized that transcellular emigration would greatly increase vascular permeability. Surprisingly, despite profound disruption of the endothelial barrier as the neutrophils moved through the cells, the changes in vascular permeability during transcellular emigration (Mac-1-/-) were not increased more than in wt mice. Instead increased vascular permeability completely tracked the number of emigrated cells and as such, permeability changes were delayed in Mac-1-/- mice. However, by 60 min neutrophils from both sets of mice were emigrating in large numbers. Electron-microscopy and spinning disk multichannel fluorescence confocal microscopy revealed endothelial docking structures that progressed to dome-like structures completely covering wt and Mac-1-/- neutrophils. These domes completely enveloped the emigrating neutrophils in both wt and Mac-1-/- mice making the mode of emigration underneath these structures extraneous to barrier function. In conclusion, predominantly paracellular versus predominantly transcellular emigration does not affect vascular barrier integrity as endothelial dome-like structures retain barrier function.

  6. Intracellular localization of lipoplexed siRNA in vascular endothelial cells of different mouse tissues.

    Science.gov (United States)

    Aleku, Manuela; Fisch, Gerald; Möpert, Kristin; Keil, Oliver; Arnold, Wolfgang; Kaufmann, Jörg; Santel, Ansgar

    2008-05-01

    Liposomally formulated siRNA can be used for RNAi applications in vivo. Intravenous bolus administration of lipoplexed siRNA has been shown to reduce gene expression in the vascular endothelium. Here, we applied immunofluorescence staining for different endothelial markers (PECAM-1, CD34, laminin) on paraffin sections to compare the respective expression pattern with the intracellular localization of intravenously administered, fluorescently labeled siRNA (siRNA-Cy3-lipoplex). By confocal microscopy, lipoplexed siRNA-Cy3 was detected inside vascular endothelial cells in vivo, which where identified with co-staining of endothelial markers. Consequently, the finding of intracellular siRNA uptake by vascular endothelial cells correlated with RNAi based specific protein reduction in situ as revealed by PECAM-1 specific immunofluorescence staining in lung tissue sections. Therefore, by using a cell biological approach these in situ data emphasize the functional uptake of liposomal siRNA molecules in vascular endothelial cells of different mouse tissues as indicated in our previous molecular study.

  7. Vascular Endothelial Growth Factor-A Is Associated with Chronic Mountain Sickness in the Andean Population

    OpenAIRE

    Espinoza, Jose R.; Alvarez, Giancarlo; León-Velarde, Fabiola; Ju Preciado, Hugo F.; Macarlupu, Jose-Luis; Rivera-Ch, Maria; Rodriguez, Jorge; Favier, Judith; Gimenez-Roqueplo, Anne-Paule; Richalet, Jean-Paul

    2014-01-01

    Espinoza, Jose R., Giancarlo Alvarez, Fabiola León-Velarde, Hugo F. Ju Preciado, Jose-Luis Macarlupu, Maria Rivera-Ch, Jorge Rodriguez, Judith Favier, Anne-Paule Gimenez-Roqueplo, and Jean-Paul Richalet. Vascular endothelial growth factor-A is associated with chronic mountain sickness in Andean population. High Alt Med Biol. 15:146–154, 2014.—A study of chronic mountain sickness (CMS) with a candidate gene—vascular endothelial growth factor A (VEGFA)—was carried out in a Peruvian population l...

  8. Reciprocal interactions between endothelial cells and macrophages in angiogenic vascular niches

    Energy Technology Data Exchange (ETDEWEB)

    Baer, Caroline; Squadrito, Mario Leonardo [The Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne (Switzerland); Iruela-Arispe, M. Luisa, E-mail: arispe@mcdb.ucla.edu [The Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne (Switzerland); Department of Molecular, Cell and Developmental Biology and Molecular Biology Institute, University of California, Los Angeles 90095, CA (United States); De Palma, Michele, E-mail: michele.depalma@epfl.ch [The Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne (Switzerland)

    2013-07-01

    The ability of macrophages to promote vascular growth has been associated with the secretion and local delivery of classic proangiogenic factors (e.g., VEGF-A and proteases). More recently, a series of studies have also revealed that physical contact of macrophages with growing blood vessels coordinates vascular fusion of emerging sprouts. Interestingly, the interactions between macrophages and vascular endothelial cells (ECs) appear to be bidirectional, such that activated ECs also support the expansion and differentiation of proangiogenic macrophages from myeloid progenitors. Here, we discuss recent findings suggesting that dynamic angiogenic vascular niches might also exist in vivo, e.g. in tumors, where sprouting blood vessels and immature myeloid cells like monocytes engage in heterotypic interactions that are required for angiogenesis. Finally, we provide an account of emerging mechanisms of cell-to-cell communication that rely on secreted microvesicles, such as exosomes, which can offer a vehicle for the rapid exchange of molecules and genetic information between macrophages and ECs engaged in angiogenesis. -- Highlights: • Macrophages promote angiogenesis by secreting proangiogenic factors. • Macrophages modulate angiogenesis via cell-to-cell contacts with endothelial cells. • Endothelial cells promote the differentiation of proangiogenic macrophages. • Macrophages and endothelial cells may cooperate to form angiogenic vascular niches.

  9. [Impact of premature birth on long term cardio-cerebral vascular events of puerpera].

    Science.gov (United States)

    Li, Dongqing; Tao, Jie; Dong, Yan; Zhao, Haiyan; Gao, Xinying; Ji, Chunpeng; Wang, Lijiao; Xiang, Honghu; Wu, Shouling

    2014-07-01

    To investigate the impact of premature birth on long term cardio-cerebral vascular events of puerpera. Ambispective cohort study method was used and 3 659 pregnant women giving birth during October 1976 to December 2008 at Kailuan medical group were included and divided into premature birth (PTB) group (n = 226) and non-PTB (NPTB) group (n = 3 433) by the history of PTB. Incidence of cardio-cerebral vascular events (myocardial infarction, cerebral infarction and cerebral hemorrhage) was obtained during follow-up. Multivariable Cox proportional hazards regression models was used to assess the relative risk of cardio-cerebral vascular events. (1) The childbearing age, proportion of pregnancy-induced hypertension, systolic blood pressure and diastolic blood pressure before delivery were significantly higher while weight and height of newborn were significantly less in PTB group than in NPTB group (P < 0.05 or 0.01). (2) There were 71 cardio-cerebral vascular events during the follow-up of (15.19 ± 7.75) years. In PTB group, the incidence of cardio-cerebral vascular events and myocardial infarction was 3.23/1 000 person-years and 2.05/1 000 person-years, respectively, while the corresponding incidence was 1.15/1 000 person-years and 0.42/1 000 person-years, respectively in NPTB group (all P < 0.05). After adjustment for other traditional cardiovascular risk factors, the risk of total cardio-cerebral vascular events, myocardial infarction in PTB group was 2.03 fold (95% CI: 1.02-4.04, P = 0.002) and 3.11 fold (95% CI: 1.18-8.18, P < 0.001) higher than in NPTB group. PTB is an independent risk factor for total cardio-cerebral vascular events, especially myocardial infarction of puerpera.

  10. A biphasic endothelial stress-survival mechanism regulates the cellular response to vascular endothelial growth factor A

    Energy Technology Data Exchange (ETDEWEB)

    Latham, Antony M.; Odell, Adam F. [Endothelial Cell Biology Unit, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT (United Kingdom); Mughal, Nadeem A. [Leeds Vascular Institute, Leeds General Infirmary, Great George Street, Leeds LS1 3EX (United Kingdom); Issitt, Theo; Ulyatt, Clare; Walker, John H. [Endothelial Cell Biology Unit, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT (United Kingdom); Homer-Vanniasinkam, Shervanthi [Leeds Vascular Institute, Leeds General Infirmary, Great George Street, Leeds LS1 3EX (United Kingdom); Ponnambalam, Sreenivasan, E-mail: s.ponnambalam@leeds.ac.uk [Endothelial Cell Biology Unit, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT (United Kingdom)

    2012-11-01

    Vascular endothelial growth factor A (VEGF-A) is an essential cytokine that regulates endothelial function and angiogenesis. VEGF-A binding to endothelial receptor tyrosine kinases such as VEGFR1 and VEGFR2 triggers cellular responses including survival, proliferation and new blood vessel sprouting. Increased levels of a soluble VEGFR1 splice variant (sFlt-1) correlate with endothelial dysfunction in pathologies such as pre-eclampsia; however the cellular mechanism(s) underlying the regulation and function of sFlt-1 are unclear. Here, we demonstrate the existence of a biphasic stress response in endothelial cells, using serum deprivation as a model of endothelial dysfunction. The early phase is characterized by a high VEGFR2:sFlt-1 ratio, which is reversed in the late phase. A functional consequence is a short-term increase in VEGF-A-stimulated intracellular signaling. In the late phase, sFlt-1 is secreted and deposited at the extracellular matrix. We hypothesized that under stress, increased endothelial sFlt-1 levels reduce VEGF-A bioavailability: VEGF-A treatment induces sFlt-1 expression at the cell surface and VEGF-A silencing inhibits sFlt-1 anchorage to the extracellular matrix. Treatment with recombinant sFlt-1 inhibits VEGF-A-stimulated in vitro angiogenesis and sFlt-1 silencing enhances this process. In this response, increased VEGFR2 levels are regulated by the phosphatidylinositol-3-kinase and PKB/Akt signaling pathways and increased sFlt-1 levels by the ERK1/2 signaling pathway. We conclude that during serum withdrawal, cellular sensing of environmental stress modulates sFlt-1 and VEGFR2 levels, regulating VEGF-A bioavailability and ensuring cell survival takes precedence over cell proliferation and migration. These findings may underpin an important mechanism contributing to endothelial dysfunction in pathological states. -- Highlights: Black-Right-Pointing-Pointer Endothelial cells mount a stress response under conditions of low serum. Black

  11. ESTUDIO DEL EFECTO DE LA CRANEOACUPUNTURA EN PACIENTES CON ENFERMEDAD VASCULAR CEREBRAL. (EVC)

    OpenAIRE

    PEREZ BRAVO, MIGUEL

    2009-01-01

    LA ENFERMEDAD VASCULAR CEREBRAL (EVC) EN MEXICO ES UN IMPORTANTE PROBLEMA DE SALUD PUBLICA, ES LA TERCERA CAUSA DE MUERTE Y LA SEGUNDA EN PRODUCIR INCAPACIDAD NEUROLOGICA. EL OBJETIVO DE ESTE ESTUDIO FUE EVALUAR EL EFECTO DE LA CRANEOACUPUNTURA EN PACIENTES CON ENFERMEDAD VASCULAR CEREBRAL (ZHONG FENG). EL PRESENTE ES UN ESTUDIO EXPERIMENTAL, PROSPECTIVO Y LONGITUDINAL, REALIZADO EN EL HOSPITAL DEL ISSSTE DE LA CIUDAD DE PUEBLA, A UN GRUPO DE 11 PACIENTES DE AMBOS SEXOS, CON...

  12. ESTUDIO DEL EFECTO DE LA CRANEOACUPUNTURA EN PACIENTES CON ENFERMEDAD VASCULAR CEREBRAL. (EVC)

    OpenAIRE

    PEREZ BRAVO, MIGUEL

    2009-01-01

    LA ENFERMEDAD VASCULAR CEREBRAL (EVC) EN MEXICO ES UN IMPORTANTE PROBLEMA DE SALUD PUBLICA, ES LA TERCERA CAUSA DE MUERTE Y LA SEGUNDA EN PRODUCIR INCAPACIDAD NEUROLOGICA. EL OBJETIVO DE ESTE ESTUDIO FUE EVALUAR EL EFECTO DE LA CRANEOACUPUNTURA EN PACIENTES CON ENFERMEDAD VASCULAR CEREBRAL (ZHONG FENG). EL PRESENTE ES UN ESTUDIO EXPERIMENTAL, PROSPECTIVO Y LONGITUDINAL, REALIZADO EN EL HOSPITAL DEL ISSSTE DE LA CIUDAD DE PUEBLA, A UN GRUPO DE 11 PACIENTES DE AMBOS SEXOS, CON...

  13. Correction of vegetative-vascular regulation in cerebral palsy by means of sports games.

    Directory of Open Access Journals (Sweden)

    Kucherov D.S.

    2011-08-01

    Full Text Available The peculiarities of the physical rehabilitation of sports facilities aimed at correcting the condition of vegetative-vascular regulation of children with cerebral palsy at the age of 11-13 years. The results of heart rate variability. The positive effects of the application of physical rehabilitation with elements of sports in children with cerebral palsy, effective changes in the state of vegetative-vascular regulation and improvement of cardiac regulation.

  14. Presión arterial sistólica y pronóstico funcional en pacientes con enfermedad vascular cerebral aguda: Registro mexicano de enfermedad vascular cerebral

    OpenAIRE

    Baños-González,Manuel; Cantú-Brito,Carlos; Chiquete,Erwin; Arauz, Antonio; Ruiz-Sandoval,José Luís; Villarreal-Careaga,Jorge; Barinagarrementeria,Fernando; Lozano,José Juan

    2011-01-01

    Objetivo: Analizar la asociación de la presión arterial sistólica (PAS) al ingreso hospitalario y la evolución clínica a 30 días en pacientes con enfermedad vascular cerebral (EVC) aguda. Métodos: El REgistro NAcional Mexicano de Enfermedad VAScular Cerebral (RENAMEVASC) es un registro hospitalario multicéntrico realizado de noviembre de 2002 a octubre de 2004. Se registraron 2000 pacientes con distintos síndromes clínicos de EVC aguda confirmados por neuroimagen. La estratificación de la evo...

  15. Presión arterial sistólica y pronóstico funcional en pacientes con enfermedad vascular cerebral aguda: Registro mexicano de enfermedad vascular cerebral

    OpenAIRE

    Baños-González,Manuel; Cantú-Brito, Carlos; Chiquete, Erwin; Arauz, Antonio; Ruiz-Sandoval,José Luís; Villarreal-Careaga,Jorge; Barinagarrementeria,Fernando; Lozano,José Juan

    2011-01-01

    Objetivo: Analizar la asociación de la presión arterial sistólica (PAS) al ingreso hospitalario y la evolución clínica a 30 días en pacientes con enfermedad vascular cerebral (EVC) aguda. Métodos: El REgistro NAcional Mexicano de Enfermedad VAScular Cerebral (RENAMEVASC) es un registro hospitalario multicéntrico realizado de noviembre de 2002 a octubre de 2004. Se registraron 2000 pacientes con distintos síndromes clínicos de EVC aguda confirmados por neuroimagen. La estratificación de la evo...

  16. Cloning, large-scale production, and purification of active dimeric rat vascular endothelial growth factor (rrVEGF-164).

    NARCIS (Netherlands)

    Geutjes, P.J.; Nillesen, S.T.M.; Lammers, G.; Daamen, W.F.; Kuppevelt, A.H.M.S.M. van

    2010-01-01

    Large-scale production of recombinant rat vascular endothelial growth factor (rrVEGF-164) is desirable for angiogenic studies. In this study, biologically active recombinant rat vascular endothelial growth factor (rrVEGF-164) was cloned and expressed in the yeast Pichia pastoris, and large-scale pro

  17. Endothelial Nitric Oxide Mediates Caffeine Antagonism of Alcohol-Induced Cerebral Artery Constriction.

    Science.gov (United States)

    Chang, Jennifer; Fedinec, Alexander L; Kuntamallappanavar, Guruprasad; Leffler, Charles W; Bukiya, Anna N; Dopico, Alex M

    2016-01-01

    Despite preventive education, the combined consumption of alcohol and caffeine (particularly from "energy drinks") continues to rise. Physiologic perturbations by separate intake of ethanol and caffeine have been widely documented. However, the biologic actions of the alcohol-caffeine combination and their underlying subcellular mechanisms have been scarcely studied. Using intravital microscopy on a closed-cranial window and isolated, pressurized vessels, we investigated the in vivo and in vitro action of ethanol-caffeine mixtures on cerebral arteries from rats and mice, widely recognized models to address cerebrovascular pathophysiology and pharmacology. Caffeine at concentrations found in human circulation after ingestion of one to two cups of coffee (10 µM) antagonized the endothelium-independent constriction of cerebral arteries evoked by ethanol concentrations found in blood during moderate-heavy alcohol intoxication (40-70 mM). Caffeine antagonism against alcohol was similar whether evaluated in vivo or in vitro, suggesting independence of systemic factors and drug metabolism, but required a functional endothelium. Moreover, caffeine protection against alcohol increased nitric oxide (NO•) levels over those found in the presence of ethanol alone, disappeared upon blocking NO• synthase, and could not be detected in pressurized cerebral arteries from endothelial nitric-oxide synthase knockout (eNOS(-/-)) mice. Finally, incubation of de-endothelialized cerebral arteries with the NO• donor sodium nitroprusside (10 µM) fully restored the protective effect of caffeine. This study demonstrates for the first time that caffeine antagonizes ethanol-induced cerebral artery constriction and identifies endothelial NO• as the critical caffeine effector on smooth muscle targets. Conceivably, situations that perturb endothelial function and/or NO• availability will critically alter caffeine antagonism of alcohol-induced cerebrovascular constriction without

  18. Sobrecarga dos cuidadores de idosos com acidente vascular cerebral

    Directory of Open Access Journals (Sweden)

    Roberta Amorim Pereira

    2013-02-01

    Full Text Available O objetivo deste estudo foi avaliar a sobrecarga dos cuidadores de idosos com acidente vascular cerebral (AVC, assim como correlacioná-la com as horas de cuidado, a idade e a independência funcional dos idosos. Trata-se de estudo transversal feito com 62 idosos com AVC e seus cuidadores. O instrumento continha variáveis sociodemográficas e econômicas, Mini-Exame do Estado Mental, Medida da Independência Funcional (MIF e a Escala de Zarit. A possível correlação entre os escores da escala de Zarit e as outras variáveis foi avaliada por meio do Coeficiente de Correlação de Pearson. A maioria dos cuidadores era adultos, filhos, casados e do sexo feminino. A média do escore de Zarit foi 34,92 (15,8. A MIF apresentou correlação negativa com a sobrecarga do cuidador, porém, não houve correlação com a idade e as horas de cuidado. A sobrecarga da maioria dos cuidadores variou de moderada a severa e parece estar relacionada ao nível de independência funcional dos idosos.

  19. Sobrecarga dos cuidadores de idosos com acidente vascular cerebral

    Directory of Open Access Journals (Sweden)

    Roberta Amorim Pereira

    Full Text Available O objetivo deste estudo foi avaliar a sobrecarga dos cuidadores de idosos com acidente vascular cerebral (AVC, assim como correlacioná-la com as horas de cuidado, a idade e a independência funcional dos idosos. Trata-se de estudo transversal feito com 62 idosos com AVC e seus cuidadores. O instrumento continha variáveis sociodemográficas e econômicas, Mini-Exame do Estado Mental, Medida da Independência Funcional (MIF e a Escala de Zarit. A possível correlação entre os escores da escala de Zarit e as outras variáveis foi avaliada por meio do Coeficiente de Correlação de Pearson. A maioria dos cuidadores era adultos, filhos, casados e do sexo feminino. A média do escore de Zarit foi 34,92 (15,8. A MIF apresentou correlação negativa com a sobrecarga do cuidador, porém, não houve correlação com a idade e as horas de cuidado. A sobrecarga da maioria dos cuidadores variou de moderada a severa e parece estar relacionada ao nível de independência funcional dos idosos.

  20. Occupational performance and satisfaction of individuals after cerebral vascular accident

    Directory of Open Access Journals (Sweden)

    Kátia Vanessa Pinto de Meneses

    2014-12-01

    Full Text Available Introduction: Scientific studies show that occupational therapy interventions with patients after cerebral vascular accident (CVA - post-stroke patients, help them resume the performance of important meaningful tasks. Objective: To measure changes in the perception of post-stroke patients on their occupational performance and satisfaction after the intervention of occupational therapy. Methodology: An observational, longitudinal, prospective study with CVA patients treated at occupational therapy service at the ‘Unidade Mista de Taguatinga’, Federal District, Brazil. The Canadian Occupational Performance Measure (COPM was applied in three distinct times: during the initial assessment (time 1, after 3 months (time 2, and after 6 months (time 3 of occupational therapy intervention. Results: The analysis after 3 months of intervention was performed with 17 patients; all showed increased performance scores (p = 0.000, and only one patient presented decrease in satisfaction scores. The analysis after 6 months was conducted with 13 patients; all showed significant improvement (p = 0.000 in scores for performance and satisfaction. Conclusions: The study shows the improvement in satisfaction and occupational performance of CVA patients after occupational therapy intervention. The study suggests that occupational therapy intervention helps the rehabilitation process of post-stroke patients, enabling them to improve their occupational performance and satisfaction and, consequently, their independence.

  1. Akita spontaneously type 1 diabetic mice exhibit elevated vascular arginase and impaired vascular endothelial and nitrergic function.

    Directory of Open Access Journals (Sweden)

    Haroldo A Toque

    Full Text Available BACKGROUND: Elevated arginase (Arg activity is reported to be involved in diabetes-induced vascular endothelial dysfunction. It can reduce L-arginine availability to nitric oxide (NO synthase (NOS and NO production. Akita mice, a genetic non-obese type 1 diabetes model, recapitulate human diabetes. We determined the role of Arg in a time-course of diabetes-associated endothelial dysfunction in aorta and corpora cavernosa (CC from Akita mice. METHODS AND RESULTS: Endothelium-dependent relaxation, Arg and NOS activity, and protein expression levels of Arg and constitutive NOS were assessed in aortas and CC from Akita and non-diabetic wild type (WT mice at 4, 12 and 24 wks of age. Systolic blood pressure (SBP was assessed by tail cuff. In aorta and CC, Akita mice exhibited a progressive impairment of vascular endothelial and nitrergic function increased Arg activity and expression (Arg1 in aorta and both Arg1 and Arg2 in CC compared with that of age-matched WT mice. Treatment of aorta and CC from Akita mice with an Arg inhibitor (BEC or ABH reduced diabetes-induced elevation of Arg activity and restored endothelial and nitrergic function. Reduced levels of phospho-eNOS at Ser(1177 (in aorta and CC and nNOS expression (in CC were observed in Akita mice at 12 and 24 wks. Akita mice also had decreased NOS activity in aorta and CC at 12 and 24 wks that was restored by BEC treatment. Further, Akita mice exhibited moderately increased SBP at 24 wks and increased sensitivity to PE-induced contractions in aorta and sympathetic nerve stimulation in CC at 12 and 24 wks. CONCLUSIONS: Over 24 wks of diabetes in Akita mice, both aortic and cavernosal tissues exhibited increased Arg activity/expression, contributing to impaired endothelial and nitrergic function and reduced NO production. Our findings demonstrate involvement of Arg activity in diabetes-induced impairment of vascular function in Akita mouse.

  2. Cerebral vascular effects of hypovolemia and dopamine infusions

    DEFF Research Database (Denmark)

    Holst Hahn, Gitte; Heiring, Christian; Pryds, Ole

    2012-01-01

    Despite widespread use, effects of volume boluses and dopamine in hypotensive newborn infants remain controversial. We aimed to elucidate if hypovolemia alone impairs cerebral autoregulation (CA) and if dopamine affects cerebral vasculature.......Despite widespread use, effects of volume boluses and dopamine in hypotensive newborn infants remain controversial. We aimed to elucidate if hypovolemia alone impairs cerebral autoregulation (CA) and if dopamine affects cerebral vasculature....

  3. Effects of Panax notoginseng saponins on vascular endothelial cells in vitro

    Institute of Scientific and Technical Information of China (English)

    關超然; 關加荤

    2000-01-01

    AIM: To investigate the inhibition of endothelium-dependent in vitro vascular relaxation induced by the total saponins (gensenosides) from Panax notoginseng ( PNS ) and the effect of PNS on the cytosolic Ca2 + concentration on cultured bovine pulmonary artery endothelial cells.METHODS: The endothelial-dependent vascular relaxation was assessed using acetylcholine (ACh) or cyclopiazonic acid (CPA) induced relaxation in endothelium-intact rat aorta. Cytosolic Caa + level was assessed in real time using dynamic digital fluorescence ratio imaging.RESULTS: In addition to its direct relaxation of the smooth muscle cells at high concentrations, PNS, at 100 mg/L having little effect on smooth muscle, caused a marked inhibition of endothelium-dependent relaxation brought about by PNS. This inhibitory effect was due to its inhibition of elevation of cytosolic Ca2 + , which is required for the activation of NO generation and release from the vascular endothelial cells. Nifedipine has no effect on either the endothelium-dependent relaxation or the cytosolic Ca2 + level in the cultured endothelial cells.CONCLUSION: Our findings are consistent with the known action of PNS on receptor-operated Ca2 + channels and support our contention that PNS inhibits endotheliumdependent relaxation by preventing the increase of Ca2 + level in endothelial cells via the receptor-operated Ca2 + channels in the presence of ACh or the non-selective cation channels opened by CPA.

  4. Endothelial glycocalyx shedding and vascular permeability in severely injured trauma patients

    DEFF Research Database (Denmark)

    Rahbar, Elaheh; Cardenas, Jessica C; Baimukanova, Gyulnar

    2015-01-01

    BACKGROUND: The endothelial glycocalyx layer (EGL) is a key regulator of vascular permeability, cell adhesion, and inflammation. The EGL is primarily composed of syndecan-1, hyaluronic acid (HA), heparan sulfate (HS) and chondroitin sulfate (CS). While many studies have observed increased sheddin...

  5. Formyl Peptide Receptor Activation Elicits Endothelial Cell Contraction and Vascular Leakage.

    Science.gov (United States)

    Wenceslau, Camilla F; McCarthy, Cameron G; Webb, R Clinton

    2016-01-01

    The major pathophysiological characteristic of systemic inflammatory response syndrome (SIRS) and sepsis is the loss of control of vascular tone and endothelial barrier dysfunction. These changes are attributed to pro-inflammatory mediators. It has been proposed that in patients and rats without infection, cell components from damaged tissue are the primary instigators of vascular damage. Mitochondria share several characteristics with bacteria, and when fragments of mitochondria are released into the circulation after injury, they are recognized by the innate immune system. N-Formyl peptides are common molecular signatures of bacteria and mitochondria and are known to play a role in the initiation of inflammation by activating the formyl peptide receptor (FPR). We have demonstrated that infusion of mitochondrial N-formyl peptides (F-MIT) leads to sepsis-like symptoms, including vascular leakage. We have also observed that F-MIT, via FPR activation, elicits changes in cytoskeleton-regulating proteins in endothelial cells. Therefore, we hypothesize that these FPR-mediated changes in cytoskeleton can cause endothelial cell contraction and, consequently vascular leakage. Here, we propose that endothelial FPR is a key contributor to impaired barrier function in SIRS and sepsis patients following trauma.

  6. Erythropoietin and vascular endothelial growth factor as risk markers for severe hypoglycaemia in type 1 diabetes

    DEFF Research Database (Denmark)

    Kristensen, P L; Pedersen-Bjergaard, U; Schalkwijk, C

    2010-01-01

    OBJECTIVE: Circulating erythropoietin (EPO) and vascular endothelial growth factor (VEGF) increase during hypoglycaemia and may represent protective hormonal counter-regulatory responses. We tested the hypothesis that low levels of EPO and VEGF are associated with a higher frequency of severe...... levels to determine future risk of severe hypoglycaemia in people with type 1 diabetes....

  7. RNA interference inhibits expression of vascular endothelial growth factor (VEGF) in human retinal pigment epithelial cells

    Institute of Scientific and Technical Information of China (English)

    CAI Chun-mei; SUN Bao-chen; LIU Xu-yang; WANG Jin-jin; LI Jun-fa; HAN Song; WANG Ning-li; LU Qing-jun

    2005-01-01

    @@ Choroidal neovascularization (CNV), a major cause of vision loss, is the result of the increased vascular endothelial growth factor (VEGF) expression in human retinal pigment epithelial (RPE) cells. It is important to inhibit the expression of VEGF protein in RPE cells.

  8. INTRAOCULAR AND SERUM LEVELS OF VASCULAR ENDOTHELIAL GROWTH FACTOR IN ACUTE RETINAL NECROSIS AND OCULAR TOXOPLASMOSIS

    NARCIS (Netherlands)

    Wiertz, Karin; De Visser, Lenneke; Rijkers, Ger; De Groot-Mijnes, Jolanda; Los, Leonie; Rothova, Aniki

    2010-01-01

    Purpose: To determine the intraocular and serum vascular endothelial growth factor (VEGF) levels in patients with acute retinal necrosis (ARN) and compare those with VEGF levels found in patients with ocular toxoplasmosis (OT). Methods: Paired intraocular fluid and serum samples of 17 patients with

  9. Relationship between dyslipidemia and vascular endothelial function in patients with coronary artery spasm

    Institute of Scientific and Technical Information of China (English)

    向定成

    2006-01-01

    Objectives To investigate the effects of dyslipidemia on vascular endothelial function in patients with coronary artery spasm. Methods Sixty-four patients with chest pain but without significant angiographic stenosis were divided into coronary spasm group (n=46 with coronary spasm) and control group (n=18 without coronary spasm) according to acetylcholine provoking test. Endothelin-1 (ET-1), nitric oxide (NO) and lipids were

  10. Intraocular and systemic levels of vascular endothelial growth factor in advanced cases of retinopathy of prematurity

    Science.gov (United States)

    Velez-Montoya, Raul; Clapp, Carmen; Rivera, Jose Carlos; Garcia-Aguirre, Gerardo; Morales-Cantón, Virgilio; Fromow-Guerra, Jans; Guerrero-Naranjo, Jose Luis; Quiroz-Mercado, Hugo

    2010-01-01

    Purpose: To measure vitreous, aqueous, subretinal fluid and plasma levels of vascular endothelial growth factor in late stages of retinopathy of prematurity. Methods: Interventional study. We enrolled patients with clinical diagnoses of bilateral stage V retinopathy of prematurity, confirmed by b-scan ultrasound and programmed for vitrectomy. During surgery we took samples from blood, aqueous, vitreous, and subretinal fluids. The vascular endothelial growth factor concentration in each sample was measured by ELISA reaction. A control sample of aqueous, vitreous and blood was taken from patients with congenital cataract programmed for phacoemulsification. For statistical analysis, a Mann–Whitney and a Wilcoxon W test was done with a significant P value of 0.05. Results: We took samples of 16 consecutive patients who met the inclusion criteria. The vascular endothelial growth factor levels in the study group were: aqueous, 76.81 ± 61.89 pg/mL; vitreous, 118.53 ± 65.87 pg/mL; subretinal fluid, 1636.58 ± 356.47 pg/mL; and plasma, 74.64 ± 43.94 pg/mL. There was a statistical difference between the study and the control group (P < 0.001) in the aqueous and vitreous samples. Conclusion: Stage 5 retinopathy of prematurity has elevated intraocular levels of vascular endothelial growth factor, which remains high despite severe retinal lesion. There was no statistical difference in plasma levels of the molecule between the control and study group. PMID:20856587

  11. Augmentation of radiation response by motesanib, a multikinase inhibitor that targets vascular endothelial growth factor receptors.

    NARCIS (Netherlands)

    Kruser, T.J.; Wheeler, D.L.; Armstrong, E.A.; Iida, M.; Kozak, K.R.; Kogel, A.J. van der; Bussink, J.; Coxon, A.; Polverino, A.; Harari, P.M.

    2010-01-01

    BACKGROUND: Motesanib is a potent inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, platelet-derived growth factor receptor, and Kit receptors. In this report we examine the interaction between motesanib and radiation in vitro and in head and neck squamous cell carcinoma

  12. Tumor MMP-1 Activates Endothelial PAR1 to Facilitate Vascular Intravasation and Metastatic Dissemination

    DEFF Research Database (Denmark)

    Juncker-Jensen, Anna; Deryugina, Elena I; Rimann, Ivo

    2013-01-01

    non-tumor-cell/non-matrix target, activation of which by carcinoma-produced MMP-1 regulates endothelial permeability and transendothelial migration. The inhibitory effects of specific PAR1 antagonists in live animals have also indicated that the mechanisms of MMP-1-dependent vascular permeability...

  13. Estrogen-induced DNA synthesis in vascular endothelial cells is mediated by ROS signaling

    Directory of Open Access Journals (Sweden)

    Felty Quentin

    2006-04-01

    Full Text Available Abstract Background Since estrogen is known to increase vascular endothelial cell growth, elevated estrogen exposure from hormone replacement therapy or oral contraceptives has the potential to contribute in the development of abnormal proliferative vascular lesions and subsequent thickening of the vasculature. How estrogen may support or promote vascular lesions is not clear. We have examined in this study whether estrogen exposure to vascular endothelial cells increase the formation of reactive oxygen species (ROS, and estrogen-induced ROS is involved in the growth of endothelial cells. Methods The effect of estrogen on the production of intracellular oxidants and the role of estrogen-induced ROS on cell growth was studied in human umbilical vein endothelial cells. ROS were measured by monitoring the oxidation of 2'7'-dichlorofluorescin by spectrofluorometry. Endothelial cell growth was measured by a colorimetric immunoassay based on BrdU incorporation into DNA. Results Physiological concentrations of estrogen (367 fmol and 3.67 pmol triggered a rapid 2-fold increase in intracellular oxidants in endothelial cells. E2-induced ROS formation was inhibited to basal levels by cotreatment with the mitochondrial inhibitor rotenone (2 μM and xanthine oxidase inhibitor allopurinol (50 μM. Inhibitors of NAD(PH oxidase, apocynin and DPI, did not block E2-induced ROS formation. Furthermore, the NOS inhibitor, L-NAME, did not prevent the increase in E2-induced ROS. These findings indicate both mitochondria and xanthine oxidase are the source of ROS in estrogen treated vascular endothelial cells. E2 treated cells showed a 2-fold induction of BrdU incorporation at 18 h which was not observed in cells exposed to vehicle alone. Cotreatment with ebselen (20 μM and NAC (1 mM inhibited E2-induced BrdU incorporation without affecting the basal levels of DNA synthesis. The observed inhibitory effect of NAC and ebselen on E2-induced DNA synthesis was also shown

  14. [Biological activities of exogenous polysaccharides via controlling endogenous proteoglycan metabolism in vascular endothelial cells].

    Science.gov (United States)

    Sato, Tomoko; Yamamoto, Chika; Fujiwara, Yasuyuki; Kaji, Toshiyuki

    2008-05-01

    Proteoglycan contains glycosmainoglycans, which are endogenous sulfated polysaccharides, in the molecule. The metabolism of proteoglycans regulates cell behavior and cellular events. It is possible that exogenous polysaccharide-related molecules exhibit their biological activities by two mechanisms. One is the interaction with cells and the other is the interaction with growth factors/cytokines that regulate proteoglycans. In this review, we describe sodium spirulan, a sulfated polysaccharide obtained from a hot-water extract of the blue-green alga Spirulina platensis, as an exogenous polysaccharide that stimulates the release of proteoglycans from vascular endothelial cells. Factors that regulate endothelial proteoglycan metabolism are also being described as possible target molecules of exogenous polysaccharides. Further research is required to obtain exogenous polysaccharide-related molecules that exhibit useful biological activities through controlling endothelial proteoglycan metabolism for protection against vascular lesions such as atheroslcerosis.

  15. Expression of vascular endothelial growth factor and its two receptors in normal human endometrium

    Institute of Scientific and Technical Information of China (English)

    王海燕; 陈贵安

    2003-01-01

    Objectives: We try to demonstrate the expression of vascular endothelial growthfactor (VEGF) and its receptors, flt-1 and KDR, in normal human emdometrium duringthe menstrual cycle.Methods: Immunohistochemical method was used to observe the expression ofVEGF and its two receptors in emdometrium throughout the normal menstrual cyclemeanwhile the isoforms of VEGF were also detected by Western blot analysis. The en-dothelial cells of micro-vessels were marked with Ⅷ factor antibody.Results: VEGF and its receptors existed in endometrial glandular, stromal and vas-cular endothelial cells of human endometrium. Their expressions were higher in the mid-secretory phase of menstrual cycle and highest at menstruation. VEGF121 and VEGF165were the predominant isoforms in normal human endometrium.Conclusion: The expression of VEGF and its two receptors showed cycle-dependentin human endometrium, probably involved in embryonic implantation and endometrialproliferation and differentiation.

  16. Deviation from optimal vascular caliber control at middle cerebral artery bifurcations harboring aneurysms.

    Science.gov (United States)

    Baharoglu, Merih I; Lauric, Alexandra; Wu, Chengyuan; Hippelheuser, James; Malek, Adel M

    2014-10-17

    Cerebral aneurysms form preferentially at arterial bifurcations. The vascular optimality principle (VOP) decrees that minimal energy loss across bifurcations requires optimal caliber control between radii of parent (r₀) and daughter branches (r1 and r2): r₀(n)=r₁(n)+r₂(n), with n approximating three. VOP entails constant wall shear stress (WSS), an endothelial phenotype regulator. We sought to determine if caliber control is maintained in aneurysmal intracranial bifurcations. Three-dimensional rotational angiographic volumes of 159 middle cerebral artery (MCA) bifurcations (62 aneurysmal) were processed using 3D gradient edge-detection filtering, enabling threshold-insensitive radius measurement. Radius ratio (RR)=r₀(3)/(r₁(3)+r₂(3)) and estimated junction exponent (n) were compared between aneurysmal and non-aneurysmal bifurcations using Student t-test and Wilcoxon rank-sum analysis. The results show that non-aneurysmal bifurcations display optimal caliber control with mean RR of 1.05 and median n of 2.84. In contrast, aneurysmal bifurcations had significantly lower RR (0.76, pbifurcations revealed a daughter branch larger than its parent vessel, an absolute violation of optimality, not witnessed in non-aneurysmal bifurcations. The aneurysms originated more often off the smaller daughter (52%) vs. larger daughter branch (16%). Aneurysm size was not statistically correlated to RR or n. Aneurysmal males showed higher deviation from VOP. Non-aneurysmal MCA bifurcations contralateral to aneurysmal ones showed optimal caliber control. Aneurysmal bifurcations, in contrast to non-aneurysmal counterparts, disobey the VOP and may exhibit dysregulation in WSS-mediated caliber control. The mechanism of this focal divergence from optimality may underlie aneurysm pathogenesis and requires further study.

  17. Vascular Endothelial Growth Factor-A165b Is Protective and Restores Endothelial Glycocalyx in Diabetic Nephropathy.

    Science.gov (United States)

    Oltean, Sebastian; Qiu, Yan; Ferguson, Joanne K; Stevens, Megan; Neal, Chris; Russell, Amy; Kaura, Amit; Arkill, Kenton P; Harris, Kirstie; Symonds, Clare; Lacey, Katja; Wijeyaratne, Lihini; Gammons, Melissa; Wylie, Emma; Hulse, Richard P; Alsop, Chloe; Cope, George; Damodaran, Gopinath; Betteridge, Kai B; Ramnath, Raina; Satchell, Simon C; Foster, Rebecca R; Ballmer-Hofer, Kurt; Donaldson, Lucy F; Barratt, Jonathan; Baelde, Hans J; Harper, Steven J; Bates, David O; Salmon, Andrew H J

    2015-08-01

    Diabetic nephropathy is the leading cause of ESRD in high-income countries and a growing problem across the world. Vascular endothelial growth factor-A (VEGF-A) is thought to be a critical mediator of vascular dysfunction in diabetic nephropathy, yet VEGF-A knockout and overexpression of angiogenic VEGF-A isoforms each worsen diabetic nephropathy. We examined the vasculoprotective effects of the VEGF-A isoform VEGF-A165b in diabetic nephropathy. Renal expression of VEGF-A165b mRNA was upregulated in diabetic individuals with well preserved kidney function, but not in those with progressive disease. Reproducing this VEGF-A165b upregulation in mouse podocytes in vivo prevented functional and histologic abnormalities in diabetic nephropathy. Biweekly systemic injections of recombinant human VEGF-A165b reduced features of diabetic nephropathy when initiated during early or advanced nephropathy in a model of type 1 diabetes and when initiated during early nephropathy in a model of type 2 diabetes. VEGF-A165b normalized glomerular permeability through phosphorylation of VEGF receptor 2 in glomerular endothelial cells, and reversed diabetes-induced damage to the glomerular endothelial glycocalyx. VEGF-A165b also improved the permeability function of isolated diabetic human glomeruli. These results show that VEGF-A165b acts via the endothelium to protect blood vessels and ameliorate diabetic nephropathy.

  18. Identification of nitric oxide as an endogenous inhibitor of 26S proteasomes in vascular endothelial cells.

    Directory of Open Access Journals (Sweden)

    Hongtao Liu

    Full Text Available The 26S proteasome plays a fundamental role in almost all eukaryotic cells, including vascular endothelial cells. However, it remains largely unknown how proteasome functionality is regulated in the vasculature. Endothelial nitric oxide (NO synthase (eNOS-derived NO is known to be essential to maintain endothelial homeostasis. The aim of the present study was to establish the connection between endothelial NO and 26S proteasome functionality in vascular endothelial cells. The 26S proteasome reporter protein levels, 26S proteasome activity, and the O-GlcNAcylation of Rpt2, a key subunit of the proteasome regulatory complex, were assayed in 26S proteasome reporter cells, human umbilical vein endothelial cells (HUVEC, and mouse aortic tissues isolated from 26S proteasome reporter and eNOS knockout mice. Like the other selective NO donors, NO derived from activated eNOS (by pharmacological and genetic approach increased O-GlcNAc modification of Rpt2, reduced proteasome chymotrypsin-like activity, and caused 26S proteasome reporter protein accumulation. Conversely, inactivation of eNOS reversed all the effects. SiRNA knockdown of O-GlcNAc transferase (OGT, the key enzyme that catalyzes protein O-GlcNAcylation, abolished NO-induced effects. Consistently, adenoviral overexpression of O-GlcNAcase (OGA, the enzyme catalyzing the removal of the O-GlcNAc group, mimicked the effects of OGT knockdown. Finally, compared to eNOS wild type aortic tissues, 26S proteasome reporter mice lacking eNOS exhibited elevated 26S proteasome functionality in parallel with decreased Rpt2 O-GlcNAcylation, without changing the levels of Rpt2 protein. In conclusion, the eNOS-derived NO functions as a physiological suppressor of the 26S proteasome in vascular endothelial cells.

  19. Connexins in endothelial barrier function - novel therapeutic targets countering vascular hyperpermeability.

    Science.gov (United States)

    Soon, Allyson Shook Ching; Chua, Jia Wang; Becker, David Laurence

    2016-10-28

    Prolonged vascular hyperpermeability is a common feature of many diseases. Vascular hyperpermeability is typically associated with changes in the expression patterns of adherens and tight junction proteins. Here, we focus on the less-appreciated contribution of gap junction proteins (connexins) to basal vascular permeability and endothelial dysfunction. First, we assess the association of connexins with endothelial barrier integrity by introducing tools used in connexin biology and relating the findings to customary readouts in vascular biology. Second, we explore potential mechanistic ties between connexins and junction regulation. Third, we review the role of connexins in microvascular organisation and development, focusing on interactions of the endothelium with mural cells and tissue-specific perivascular cells. Last, we see how connexins contribute to the interactions between the endothelium and components of the immune system, by using neutrophils as an example. Mounting evidence of crosstalk between connexins and other junction proteins suggests that we rethink the way in which different junction components contribute to endothelial barrier function. Given the multiple points of connexin-mediated communication arising from the endothelium, there is great potential for synergism between connexin-targeted inhibitors and existing immune-targeted therapeutics. As more drugs targeting connexins progress through clinical trials, it is hoped that some might prove effective at countering vascular hyperpermeability.

  20. Differential Gene Expression of Primary Cultured Lymphatic and Blood Vascular Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Gregory M. Nelson

    2007-12-01

    Full Text Available Blood vascular endothelial cells (BECs and the developmentally related lymphatic endothelial cells (LECs create complementary, yet distinct vascular networks. Each endothelial cell type interacts with flowing fluid and circulating cells, yet each vascular system has evolved specialized gene expression programs and thus both cell types display different phenotypes. BECs and LECs express distinct genes that are unique to their specific vascular microenvironment. Tumors also take advantage of the molecules that are expressed in these vascular systems to enhance their metastatic potential. We completed transcriptome analyses on primary cultured LECs and BECs, where each comparative set was isolated from the same individual. Differences were resolved in the expression of several major categories, such as cell adhesion molecules (CAMs, cytokines, cytokine receptors. We have identified new molecules that are associated with BECs (e.g., claudin-9, CXCL11, neurexin-1, neurexin-2, the neuronal growth factor regulator-1 and LECs (e.g., claudin-7, CD58, hyaluronan and proteoglycan link protein 1 (HAPLN1, the poliovirus receptor-related 3 molecule that may lead to novel therapeutic treatments for diseases of lymphatic or blood vessels, including metastasis of cancer to lymph nodes or distant organs.

  1. Platelet Endothelial Cell Adhesion Molecule 1 (PECAM-1/CD31): A Multifunctional Vascular Cell Adhesion Molecule.

    Science.gov (United States)

    Delisser, H M; Baldwin, H S; Albelda, S M

    1997-08-01

    PECAM-1/CD31 is a member of the immunoglobulin gene superfamily found on platelets, leukocytes, and endothelial cells, where it concentrates at cell-cell borders. It has been shown to both mediate cell-cell adhesion through homophilic and heterophilic interactions and to transduce intracellular signals that upregulate the function of integrins on leukocytes. Its cellular distribution and ability to mediate adhesive and signaling phenomena suggested that PECAM-1 was a multifunctional vascular cell adhesion molecule involved in leukocyte-endothelial and endothelial-endothelial interactions. These initial suggestions have been largely confirmed as recent studies have implicated PECAM-1 in the inflammatory process and in the formation of blood vessels. As our understanding of the molecular and functional properties of PECAM-1 grows, new insights will be gained that may have therapeutic implications for cardiovascular development and disease. (Trends Cardiovasc Med 1997;7:203-210). © 1997, Elsevier Science Inc.

  2. l-Homocysteine-induced cathepsin V mediates the vascular endothelial inflammation in hyperhomocysteinaemia.

    Science.gov (United States)

    Leng, Yi-Ping; Ma, Ye-Shuo; Li, Xiao-Gang; Chen, Rui-Fang; Zeng, Ping-Yu; Li, Xiao-Hui; Qiu, Cheng-Feng; Li, Ya-Pei; Zhang, Zhen; Chen, Alex F

    2017-06-20

    Vascular inflammation, including the expression of inflammatory cytokines in endothelial cells, plays a critical role in hyperhomocysteinaemia-associated vascular diseases. Cathepsin V, specifically expressed in humans, is involved in vascular diseases through its elastolytic and collagenolytic activities. The aim of this study was to determine the effects of cathepsin V on l-homocysteine-induced vascular inflammation. A high methionine diet-induced hyperhomocysteinaemic mouse model was used to assess cathepsin V expression and vascular inflammation. Cultures of HUVECs were challenged with l-homocysteine and the cathepsin L/V inhibitor SID to assess the pro-inflammatory effects of cathepsin V. Transfection and antisense techniques were utilized to investigate the effects of cathepsin V on the dual-specificity protein phosphatases (DUSPs) and MAPK pathways. Cathepsin L (human cathepsin V homologous) was increased in the thoracic aorta endothelial cells of hyperhomocysteinaemic mice; l-homocysteine promoted cathepsin V expression in HUVECs. SID suppressed the activity of cathepsin V and reversed the up-regulation of inflammatory cytokines (IL-6, IL-8 and TNF-α), adhesion and chemotaxis of leukocytes and vascular inflammation induced by l-homocysteine in vivo and in vitro. Increased cathepsin V promoted the degradation of DUSP6 and DUSP7, phosphorylation and subsequent nuclear translocation of ERK1/2, phosphorylation of STAT1 and expression of IL-6, IL-8 and TNF-α. This study has identified a novel mechanism, which shows that l-homocysteine-induced upregulation of cathepsin V mediates vascular endothelial inflammation under high homocysteine condition partly via ERK1/2 /STAT1 pathway. This mechanism could represent a potential therapeutic target in hyperaemia-associated vascular diseases. © 2017 The British Pharmacological Society.

  3. Circulating microparticles from Crohn's disease patients cause endothelial and vascular dysfunctions.

    Directory of Open Access Journals (Sweden)

    Daniela Leonetti

    Full Text Available BACKGROUND: Microparticles (MPs are small vesicles released during cell activation or apoptosis. They are involved in coagulation, inflammation and vascular dysfunction in several diseases. We characterized circulating MPs from Crohn's Disease (CD patients and evaluated their effects on endothelial function and vascular reactivity after in vivo injection into mice. METHODS: Circulating MPs and their cellular origins were examined by flow cytometry from blood samples from healthy subjects (HS and inactive or active CD patients. MPs were intravenously injected into mice. After 24 hours, endothelial function and vascular reactivity were assessed. RESULTS: Circulating MP levels did not differ between HS and inactive CD patients except for an increase in leukocyte-derived MPs in CD. Active CD patients compared to HS displayed increased total circulating MPs, pro-coagulant MPs and those from platelets, endothelium, erythrocytes, leukocytes, activated leukocytes and activated platelets. A significant correlation was found between total levels of MPs, those from platelets and endothelial cells, and the Harvey-Bradshaw clinical activity index. MPs from CD, but not from HS, impaired endothelium-dependent relaxation in mice aorta and flow-induced dilation in mice small mesenteric arteries, MPs from inactive CD patients being more effective than those from active patients. CDMPs induced vascular hypo-reactivity in aorta that was prevented by a nitric oxide (NO-synthase inhibitor, and was associated with a subtle alteration of the balance between NO, reactive oxygen species and the release of COX metabolites. CONCLUSIONS: We provide evidence that MPs from CD patients significantly alter endothelial and vascular function and therefore, may play a role in CD pathophysiology, at least by contributing to uncontrolled vascular-dependent intestinal damage.

  4. A novel approach to the assessment of vascular endothelial function

    Energy Technology Data Exchange (ETDEWEB)

    Sathasivam, S; Siddiqui, Z; Greenwald, S [Pathology Group, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London (United Kingdom); Phababpha, S; Sengmeuan, P; Detchaporn, P; Kukongviriyapan, U, E-mail: s.e.greenwald@qmul.ac.uk [Department of Physiology, Khon Kaen University, Khon Kaen (Thailand)

    2011-08-17

    Impaired endothelial function (EF) is associated with atherogenesis, and its quantitative assessment has prognostic value. Currently, methods based on assessing flow-mediated dilation (FMD) are technically difficult and expensive. We tested a novel way of assessing EF by measuring the time difference between pulses arriving at the middle fingers of each hand (f-f{Delta}T), whilst FMD is induced in one arm. We compared f-f{Delta}T with standard methods in healthy and diseased subjects. Our findings suggest that the proposed simple and inexpensive technique gives comparable results and has the potential to qualitatively assess EF in the clinical setting, although further work is required.

  5. Mechanisms in decorin regulation of vascular endothelial growth factor-induced human trophoblast migration and acquisition of endothelial phenotype.

    Science.gov (United States)

    Lala, Neena; Girish, Gannareddy V; Cloutier-Bosworth, Alia; Lala, Peeyush K

    2012-09-01

    Extravillous trophoblast (EVT) cells of the human placenta invade the uterine decidua and utero-placental arteries to establish an efficient exchange of key molecules between maternal and fetal blood. Trophoblast invasion is stringently regulated in situ both positively and negatively by a variety of factors at the fetal-maternal interface to maintain a healthy utero-placental homeostasis. One such factor, decorin, a transforming growth factor (TGF)-beta binding, leucine-rich proteoglycan produced by the decidua, negatively regulates EVT proliferation, migration, and invasiveness independent of TGF-beta. We reported that these decorin actions were mediated by its binding to multiple tyrosine kinase receptors, including vascular endothelial growth factor receptor (VEGFR)-2. The present study explores the mechanisms underlying decorin antagonism of VEGF (VEGF-A) stimulation of endovascular differentiation of EVT using our EVT cell line, HTR-8/SVneo. We observe that decorin inhibits VEGF-induced EVT cell migration and endothelial-like tube formation on matrigel. VEGF activates MAPKs (p38 MAPK, MEK3/6, and ERK1/2) in EVT cells, and the activation is blocked in both cases by decorin. Employing selective MAPK inhibitors, we show that both p38 and ERK pathways contribute independently to VEGF-induced EVT migration and capillary-like tube formation. VEGF upregulates the vascular endothelial (VE) markers VE-cadherin and beta-catenin in EVT and endothelial cells, and this upregulation is blocked by decorin and MAPK inhibitors. These results suggest that decorin inhibits VEGF-A stimulation of trophoblast migration and endovascular differentiation by interfering with p38 MAPK and ERK1/2 activation. Thus decorin-mediated dual impediment of endovascular differentiation of the EVT and angiogenesis may have implications for pathogenesis of preeclampsia, a hypoinvasive trophoblast disorder in pregnancy.

  6. Immunocytochemical localization of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 of the human deciduous molar tooth germ development in the human fetus.

    Science.gov (United States)

    Miwa, Yoko; Fujita, Toshiya; Sunohara, Masataka; Sato, Iwao

    2008-01-01

    Vascular endothelial growth factor (VEGF) is a key regulator of blood vessel endothelial development. We used immunohistochemical methods to demonstrate the localization of VEGF and its receptors, showing the specific expression pattern of VEGF and VEGF receptor in the human deciduous tooth from the cap to late bell stages in the human fetus. Immunoreactivity to VEGF and its receptor VEGF receptor-2 (VEGFR-2) was intensely positive in the inner enamel epithelium at the cap stage and ranged from negative to moderately positive in the bell stage. At the late bell stage, VEGF immunoreactivity was mainly positive but weak for VEGFR-2. The intensity of VEGF and VEGFR-2 in odontoblasts increases from cap stage to late bell stage. We postulate that the dissimilar expression of VEGF in inner enamel epithelium, ameloblast and odontoblast during each stage of human tooth development may affect tooth germ formation.

  7. Generation of Functional Blood Vessels from a Single c-kit+ Adult Vascular Endothelial Stem Cell

    Science.gov (United States)

    Fang, Shentong; Wei, Jing; Pentinmikko, Nalle; Leinonen, Hannele; Salven, Petri

    2012-01-01

    In adults, the growth of blood vessels, a process known as angiogenesis, is essential for organ growth and repair. In many disorders including cancer, angiogenesis becomes excessive. The cellular origin of new vascular endothelial cells (ECs) during blood vessel growth in angiogenic situations has remained unknown. Here, we provide evidence for adult vascular endothelial stem cells (VESCs) that reside in the blood vessel wall endothelium. VESCs constitute a small subpopulation within CD117+ (c-kit+) ECs capable of undergoing clonal expansion while other ECs have a very limited proliferative capacity. Isolated VESCs can produce tens of millions of endothelial daughter cells in vitro. A single transplanted c-kit-expressing VESC by the phenotype lin−CD31+CD105+Sca1+CD117+ can generate in vivo functional blood vessels that connect to host circulation. VESCs also have long-term self-renewal capacity, a defining functional property of adult stem cells. To provide functional verification on the role of c-kit in VESCs, we show that a genetic deficit in endothelial c-kit expression markedly decreases total colony-forming VESCs. In vivo, c-kit expression deficit resulted in impaired EC proliferation and angiogenesis and retardation of tumor growth. Isolated VESCs could be used in cell-based therapies for cardiovascular repair to restore tissue vascularization after ischemic events. VESCs also provide a novel cellular target to block pathological angiogenesis and cancer growth. PMID:23091420

  8. Engineering interaction between bone marrow derived endothelial cells and electrospun surfaces for artificial vascular graft applications.

    Science.gov (United States)

    Ahmed, Furqan; Dutta, Naba K; Zannettino, Andrew; Vandyke, Kate; Choudhury, Namita Roy

    2014-04-14

    The aim of this investigation was to understand and engineer the interactions between endothelial cells and the electrospun (ES) polyvinylidene fluoride-co-hexafluoropropylene (PVDF-HFP) nanofiber surfaces and evaluate their potential for endothelialization. Elastomeric PVDF-HFP samples were electrospun to evaluate their potential use as small diameter artificial vascular graft scaffold (SDAVG) and compared with solvent cast (SC) PVDF-HFP films. We examined the consequences of fibrinogen adsorption onto the ES and SC samples for endothelialisation. Bone marrow derived endothelial cells (BMEC) of human origin were incubated with the test and control samples and their attachment, proliferation, and viability were examined. The nature of interaction of fibrinogen with SC and ES samples was investigated in detail using ELISA, XPS, and FTIR techniques. The pristine SC and ES PVDF-HFP samples displayed hydrophobic and ultrahydrophobic behavior and accordingly, exhibited minimal BMEC growth. Fibrinogen adsorbed SC samples did not significantly enhance endothelial cell binding or proliferation. In contrast, the fibrinogen adsorbed electrospun surfaces showed a clear ability to modulate endothelial cell behavior. This system also represents an ideal model system that enables us to understand the natural interaction between cells and their extracellular environment. The research reported shows potential of ES surfaces for artificial vascular graft applications.

  9. Production of neutralizing monoclonal antibody against human vascular endothelial growth factor receptor Ⅱ

    Institute of Scientific and Technical Information of China (English)

    Rong LI; Dong-sheng XIONG; Xiao-feng SHAO; Jia LIU; Yuan-fu XU; Yuan-sheng XU; Han-zhi LIU; Zhen-ping ZHU; Chun-zheng YANG

    2004-01-01

    AIM: To prepare neutralizing monoclonal antibody (mAb) against extracellular immunoglobulin (Ig)-like domainⅢ of vascular endothelial growth factor receptor KDR and study its biological activity. METHODS: Soluble KDR Ig domain Ⅲ (KDR-Ⅲ) fusion protein was expressed in E Coli and purified from the bacterial periplasmic extracts via an affinity chromatography. Monoclonal antibodies against KDR-Ⅲ were prepared by hybridoma technique. ELISA and FACS analysis were used to identify its specificity. Immunoprecipitation and [3H]-thymidine incorporation assay were also used to detect the activity of anti-KDR mAb blocking the phosphorylation of KDR tyrosine kinase receptor and the influence on vascular endothelial growth factor-induced mitogenesis of human endothelial ceils.RESULTS: A monoclonal antibody, Ycom1D3 (IgG1), was generated from a mouse immunized with the recombinant KDR-Ⅲ protein. Ycom1D3 bound specifically to both the soluble KDR-Ⅲ and the cell-surface expressed KDR. Ycom1D3 effectively blocked VEGF/KDR interaction and inhibited VEGF-stimulated KDR activation in human endothelial cells. Furthermore, the antibody efficiently neutralized VEGF-induced mitogenesis of human endothelial cells. CONCLUSION: Our results suggest that the anti-KDR mAb, Ycom1D3, has potential applications in the treatment of cancer and other diseases where pathological angiogenesis is involved.

  10. Improving hemocompatibility and accelerating endothelialization of vascular stents by a copper-titanium film.

    Science.gov (United States)

    Liu, Hengquan; Pan, Changjiang; Zhou, Shijie; Li, Junfeng; Huang, Nan; Dong, Lihua

    2016-12-01

    Bio-inorganic films and drug-eluting coatings are usually used to improve the hemocompatibility and inhibit restenosis of vascular stent; however, above bio-performances couldn't combine together with single materials. In the present study, we reported a simple approach to fabricate a metal film with the aim of imparting the stent with good blood compatibility and accelerating endothelialization. The films with various ratios of Cu and Ti were prepared through the physical vapor deposition. Phase structure and element composition were investigated by X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS), respectively. The releasing volume of copper ion in Cu/Ti film was determined by immersing test. The hemolysis ratio, platelet adhesion and clotting time were applied to evaluate the hemocompatibility. The proliferative behaviors of endothelial cells and smooth muscle cells under certain copper concentration were investigated in vitro and in vivo. Results indicated that copper-titanium films exhibited good hemocompatibility in vitro; however, the increase of Cu/Ti ratio could lead to increasing hemolysis ratio. Endothelial cells displayed more proliferative than smooth muscle cells when the copper concentration was film with low copper in vivo was observed at the 2nd week, indicating that the copper-titanium film with the lower copper concentration could promote endothelialization. Therefore, the inorganic copper-titanium film could be potential biomaterials to improve blood compatibility and accelerating endothelialization of vascular stents.

  11. Role of TRPM7 channels in hyperglycemia-mediated injury of vascular endothelial cells.

    Directory of Open Access Journals (Sweden)

    Huawei Sun

    Full Text Available This study investigated the change of transient receptor potential melastatin 7 (TRPM7 expression by high glucose and its role in hyperglycemia induced injury of vascular endothelial cells. Human umbilical vein endothelial cells (HUVECs were incubated in the presence or absence of high concentrations of D-glucose (HG for 72 h. RT-PCR, Real-time PCR, Western blotting, Immunofluorescence staining and whole-cell patch-clamp recordings showed that TRPM7 mRNA, TRPM7 protein expression and TRPM7-like currents were increased in HUVECs following exposure to HG. In contrast to D-glucose, exposure of HUVECs to high concentrations of L-glucose had no effect. HG increased reactive oxygen species (ROS generation, cytotoxicity and decreased endothelial nitric oxide synthase protein expression, which could be attenuated by knockdown of TRPM7 with TRPM7 siRNA. The protective effect of silencing TRPM7 against HG induced endothelial injury was abolished by U0126, an inhibitor of the extracellular signal-regulated kinase signaling pathway. These observations suggest that TRPM7 channels play an important role in hyperglycemia-induced injury of vascular endothelial cells.

  12. Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization

    NARCIS (Netherlands)

    Westenbrink, B. Daan; Lipsic, Erik; van der Meer, Peter; van der Harst, Pirn; Oeseburg, Hisko; Sarvaas, Gideon J. Du Marchie; Koster, Johan; Voors, Adriaan A.; van Veldhuisen, Dirk J.; van Gilst, Wiek H.; Schoemaker, Regien G.

    2007-01-01

    Aims Erythropoietin (EPO) improves cardiac function and induces neovascutarization in chronic heart failure (CHF), although the exact mechanism has not been elucidated. We studied the effects of EPO on homing and incorporation of endothelial progenitor cells (EPC) into the myocardial microvasculatur

  13. INTERACTIONS BETWEEN THE HUMAN GASTRIC CARCINOMA CELL AND THE HUMAN VASCULAR ENDOTHELIAL CELL

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective To definite the interactions between the human gastric carcinoma cell and the human vascular endothelial cell during the establishment and maintenance of the tumor vascular system and the tumor hematogenous metastasis.Methods We prepared the conditioned mediums of each cell so as to study the effect of the conditioned medium on itself or others by MTT colorimetry. The comprehensive effect of interactions between two cells was determined by stratified transfilter co-culture or direct contact co-culture.Results The conditioned medium of human gastric carcinoma cell can stimulate the proliferation of the human vascular endothelial cell, but the CM of HVEC can inhibit the growth of HGCC. Both kinds of cells can inhibit the growth of itself. The ultimate comprehensive effect of the interactions between two kinds of cells was increase of total cell numbers.Conclusion There exist the complicated interactions between the human gastric carcinoma cell and the human vascular endothelial cell during the tumor angiogenesis and the tumor hematogenous metastasis. The ultimate comprehensive effect of the interactions is increase of total cells numbers and tumor volume.

  14. Vascular smooth muscle cells for use in vascular tissue engineering obtained by endothelial-to-mesenchymal transdifferentiation (EnMT) on collagen matrices

    NARCIS (Netherlands)

    Krenning, Guido; Moonen, Jan-Renier A. J.; van Luyn, Marja J. A.; Harmsen, Martin C.

    2008-01-01

    The discovery of the endothelial progenitor cell (EPC) has led to an intensive research effort into progenitor cell-based tissue engineering of (small-diameter) blood vessels. Herein, EPC are differentiated to vascular endothelial cells and serve as the inner lining of bioartificial vessels. As yet,

  15. Angiogenic Type I Collagen Extracellular Matrix Integrated with Recombinant Bacteriophages Displaying Vascular Endothelial Growth Factors.

    Science.gov (United States)

    Yoon, Junghyo; Korkmaz Zirpel, Nuriye; Park, Hyun-Ji; Han, Sewoon; Hwang, Kyung Hoon; Shin, Jisoo; Cho, Seung-Woo; Nam, Chang-Hoon; Chung, Seok

    2016-01-21

    Here, a growth-factor-integrated natural extracellular matrix of type I collagen is presented that induces angiogenesis. The developed matrix adapts type I collagen nanofibers integrated with synthetic colloidal particles of recombinant bacteriophages that display vascular endothelial growth factor (VEGF). The integration is achieved during or after gelation of the type I collagen and the matrix enables spatial delivery of VEGF into a desired region. Endothelial cells that contact the VEGF are found to invade into the matrix to form tube-like structures both in vitro and in vivo, proving the angiogenic potential of the matrix.

  16. Elevated vascular endothelial growth factor in type 1 diabetic patients with diabetic nephropathy

    DEFF Research Database (Denmark)

    Hovind, P; Tarnow, L; Oestergaard, P B

    2000-01-01

    BACKGROUND: Growth factors have been suggested to play a role in the development and progression of diabetic nephropathy. Vascular endothelial growth factor (VEGF) is a potent cytokine family that induces angiogenesis and markedly increases endothelial permeability. The aim of the present study...... with normoalbuminuria, P pressure and male gender. Hemoglobin A1c and plasma VEGF did not act as predictors. No significant differences between...... patients with and without proliferative retinopathy were detected. CONCLUSIONS: Our data suggest that VEGF is elevated early in the course of diabetic nephropathy in men with type 1 diabetes mellitus. Baseline albuminuria, arterial blood pressure and male gender was predictors of diabetic nephropathy...

  17. Gene Expression Analysis of Human Vascular Endothelial Cells Treated by Ouabain in Pathological Concentration

    Institute of Scientific and Technical Information of China (English)

    任延平; 吕卓人

    2004-01-01

    Objectives To study the gene expression of human vascular endothelial cells (HUVEC) treated by ouabain in pathological concentration. Methods The response of endothelial cells to ouabain of 1.8 nmol/L was explored with a complementary DNA microarray representing 8 464 different human genes. Results The results of mRNA profiles analysis indicated that 129 of the genes were differently expressed, 26 were upregulated. Conclusions The pathological role of ouabain on HUVEC may be involved in the controlling of DNA transcription、protein translation、 metabolism and signal transduction.

  18. Role of Copper and Vascular Endothelial Growth Factor (VEGF on Endometrial Angiogenesis

    Directory of Open Access Journals (Sweden)

    Yousef Rezaei Chianeh

    2013-07-01

    Full Text Available The formation of new blood vessels is the ini-tial step in neovascularisation. The first stagein angiogenesis is the activation of endothelialcells. Copper ions stimulate proliferation andimmigration of endothelial cells. It has beenshown that serum copper concentration in-creases as the cancer disease progresses andcorrelates with tumour incidence and burden.Copper ions also activate several proangiogenicfactors, e.g., vascular endothelial growth fac-tor, basic fibroblast growth factor, andinterleukin 1. This review concerns a brief in-troduction into the basics of blood vessel de-velopment as well as the regulatory mecha-nisms of this process. The role of copper ionsin angiogenesis is discussed.

  19. Exercise training normalizes skeletal muscle vascular endothelial growth factor levels in patients with essential hypertension

    DEFF Research Database (Denmark)

    Hansen, Ane Håkansson; Nielsen, Jens Jung; Saltin, Bengt

    2010-01-01

    METHODS: Vascular endothelial growth factor (VEGF) protein and capillarization were determined in muscle vastus lateralis biopsy samples in individuals with essential hypertension (n = 10) and normotensive controls (n = 10). The hypertensive individuals performed exercise training for 16 weeks....... Muscle samples as well as muscle microdialysis fluid samples were obtained at rest, during and after an acute exercise bout, performed prior to and after the training period, for the determination of muscle VEGF levels, VEGF release, endothelial cell proliferative effect and capillarization. RESULTS......: Prior to training, the hypertensive individuals had 36% lower levels of VEGF protein and 22% lower capillary density in the muscle compared to controls. Training in the hypertensive group reduced (P

  20. Hepatocyte growth factor and vascular endothelial growth factor in ischaemic heart disease.

    Science.gov (United States)

    Suzuki, Hiroshi; Murakami, Mikitaka; Shoji, Makoto; Iso, Yoshitaka; Kondo, Takeshi; Shibata, Masayuki; Ezumi, Hitoshi; Hamazaki, Yuji; Koba, Shinji; Katagiri, Takashi

    2003-06-01

    Hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) are endothelial cell-specific growth factors, but the production of these growth factors in cardiomyocytes has also been demonstrated. However, there have been no reports focusing their attention on the changes in these growth factors after coronary intervention. We investigated the time-course changes of the serum VEGF and HGF levels in angina pectoris (AP) and acute myocardial infarction (AMI). The serum HGF and VEGF levels were measured in 60 patients with AP, in 62 patients with AMI (AP, before heparin administration, and at 24 and 48 hours, and one week after intervention; AMI, before heparin, and at 48 and 72 hours, and one, two, three and four weeks) and in 56 patients with neurocirculatory asthenia as controls. We defined the patients with remodelling who showed an increase in left ventricular end-diastolic volume index (LVEDVI) in the sub-acute phase of AMI. Hepatocyte growth factor levels in the AP and AMI were significantly higher than that in the control (p<0.0001). The AMI level was also significantly higher than AP (p<0.001). In the AMI and AP, HGF peaked at 48 hours. Vascular endothelial growth factor level in the AMI was significantly higher than that in the control and AP (p<0.0001). In the AMI, VEGF peaked at two weeks. There was a significant positive correlation between the peak VEGF and LVEDVI in the sub-acute phase of AMI (p=0.0089, r=0.436). Peak VEGF in the remodelling (+) group was significantly higher than that in the remodelling (-) group (p<0.001). In the AP, VEGF was unchanged. While both myocardial and vascular damage contribute to an increase in HGF level, vascular damage is not associated with the increase in VEGF. Vascular endothelial growth factor might be related to left ventricular remodelling in the sub-acute phase of myocardial infarction.

  1. Hyperphosphatemia, Phosphoprotein Phosphatases, and Microparticle Release in Vascular Endothelial Cells.

    Science.gov (United States)

    Abbasian, Nima; Burton, James O; Herbert, Karl E; Tregunna, Barbara-Emily; Brown, Jeremy R; Ghaderi-Najafabadi, Maryam; Brunskill, Nigel J; Goodall, Alison H; Bevington, Alan

    2015-09-01

    Hyperphosphatemia in patients with advanced CKD is thought to be an important contributor to cardiovascular risk, in part because of endothelial cell (EC) dysfunction induced by inorganic phosphate (Pi). Such patients also have an elevated circulating concentration of procoagulant endothelial microparticles (MPs), leading to a prothrombotic state, which may contribute to acute occlusive events. We hypothesized that hyperphosphatemia leads to MP formation from ECs through an elevation of intracellular Pi concentration, which directly inhibits phosphoprotein phosphatases, triggering a global increase in phosphorylation and cytoskeletal changes. In cultured human ECs (EAhy926), incubation with elevated extracellular Pi (2.5 mM) led to a rise in intracellular Pi concentration within 90 minutes. This was mediated by PiT1/slc20a1 Pi transporters and led to global accumulation of tyrosine- and serine/threonine-phosphorylated proteins, a marked increase in cellular Tropomyosin-3, plasma membrane blebbing, and release of 0.1- to 1-μm-diameter MPs. The effect of Pi was independent of oxidative stress or apoptosis. Similarly, global inhibition of phosphoprotein phosphatases with orthovanadate or fluoride yielded a global protein phosphorylation response and rapid release of MPs. The Pi-induced MPs expressed VE-cadherin and superficial phosphatidylserine, and in a thrombin generation assay, they displayed significantly more procoagulant activity than particles derived from cells incubated in medium with a physiologic level of Pi (1 mM). These data show a mechanism of Pi-induced cellular stress and signaling, which may be widely applicable in mammalian cells, and in ECs, it provides a novel pathologic link between hyperphosphatemia, generation of MPs, and thrombotic risk.

  2. The vascular endothelial growth factor expression and vascular regeneration in infarcted myocardium by skeletal muscle satellite cells

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Background Myocardial infarction results in tissue necrosis, leading to cell loss and ultimately to cardiac failure. Implantation of skeletal muscle satellite cells into the scar area may compensate for the cell loss and provides a new strategy for infarct therapy. Vascular endothelial growth factor (VEGF) is a promising reagent for inducing myocardial angiogenesis. Skeletal myoblast transplantation has been shown to improve cardiac function in chronic heart failure models by regenerating muscle. We hypothesized that VEGF expression and vascular regeneration increased in infarcted myocardium by skeletal muscle satellite cells, which can promote vascular producing and improve survival environment in infarcted myocardium.Methods The skeletal muscle satellite cells were implanted into the infarcted myocardium in a model through ligated left anterior artery in Louis Inbrad Strain rat. Specimens were got for identifying the expression of VEGF and the density of vascular by immunochemical method at two weeks after implantation. Results The proliferation and differentiation of the skeletal muscle satellite cell was very well. The expression of VEGF was higher in the implanted group (146.83±2.49) than that in the control group (134.26±6.84) (P<0.05). The vascular density in the implanted group (13.00±1.51) was also higher than that in the control (10.68±1.79) (P<0.05). Conclusion The implanted satellite cell could excrete growth factor that would induce angiogenesis and improve cell survival environment in infarcted myocardium.

  3. The targeting expression of the vascular endothelial growth factor gene in endothelial cells regulated by HRE.ppET-1

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    The success of gene therapy depends largely on the efficacy of gene delivery vector systems that can deliver genes to target organs or cells selectively and efficiently with minimal toxicity. Here, we show that by using the HRE.ppET-1 regulatory element, we were able to restrict expression of the transgene of vascular endothelial growth factor (VEGF) to endothelial cells exclusively in hypoxic conditions. Eukaryotic expression vectors such as pEGFP-HRE.ppET-1, pcDNA3.1-VEGF+Pa, pcDNA3.1-ppET-1+ EGF+Pa, and pcDNA3.1-HRE.ppET-1+VEGF+Pa were constructed by using a series of nuclear molecule handling methods like PCR, enzyme digestion. The recombinant vectors were transfected into HUVEC cells and HL7702 cells by the lipofectin method. GFP expression was observed with a fluorescence microscope to validate the specificity of expression in endothelial cells under the regulation of HRE.ppET-1 element. Cobalt chloride (final concentration 100 μmol/L) was added to the medium to mimic hypoxia in vitro. After transfection of vectors, the expression of VEGF mRNA was detected by RT-PCR, and the expression of VEGF was detected by Western blotting and ELISA methods under normoxia and hypoxia, respectively. The cell proliferation rate was detected by the MTT test. The ex- pression of GFP revealed that the exterior gene was transcripted effectively in endothelial cells regu- lated by the HRE.ppET-1 element, while the expression of GFP was very weak in nonendothelial cells. The results of RT-PCR, Western blotting and ELISA showed that VEGF gene expression in the pcDNA3.1-HRE.ppET-1+VEGF+Pa group and in the pcDNA3.1-ppET-1+VEGF+Pa group was higher in hypoxia than it was in normoxia (P<0.05). The MTT test showed that the proliferation rate of HUVEC transfected with HPVA under hypoxia exceeded that of the control group. We conclude that the HRE.ppET-1 element was expressed specifically in endothelial cells, and can increase the expression of VEGF in hypoxia and stimulate proliferation

  4. In Vivo FRET Imaging of Tumor Endothelial Cells Highlights a Role of Low PKA Activity in Vascular Hyperpermeability.

    Science.gov (United States)

    Yamauchi, Fumio; Kamioka, Yuji; Yano, Tetsuya; Matsuda, Michiyuki

    2016-09-15

    Vascular hyperpermeability is a pathological hallmark of cancer. Previous in vitro studies have elucidated roles of various signaling molecules in vascular hyperpermeability; however, the activities of such signaling molecules have not been examined in live tumor tissues for technical reasons. Here, by in vivo two-photon excitation microscopy with transgenic mice expressing biosensors based on Förster resonance energy transfer, we examined the activity of protein kinase A (PKA), which maintains endothelial barrier function. The level of PKA activity was significantly lower in the intratumoral endothelial cells than the subcutaneous endothelial cells. PKA activation with a cAMP analogue alleviated the tumor vascular hyperpermeability, suggesting that the low PKA activity in the endothelial cells may be responsible for the tumor-tissue hyperpermeability. Because the vascular endothelial growth factor (VEGF) receptor is a canonical inducer of vascular hyperpermeability and a molecular target of anticancer drugs, we examined the causality between VEGF receptor activity and the PKA activity. Motesanib, a kinase inhibitor for VEGF receptor, activated tumor endothelial PKA and reduced the vascular permeability in the tumor. Conversely, subcutaneous injection of VEGF decreased endothelial PKA activity and induced hyperpermeability of subcutaneous blood vessels. Notably, in cultured human umbilical vascular endothelial cells, VEGF activated PKA rather than decreasing its activity, highlighting the remarkable difference between its actions in vitro and in vivo These data suggested that the VEGF receptor signaling pathway increases vascular permeability, at least in part, by reducing endothelial PKA activity in the live tumor tissue. Cancer Res; 76(18); 5266-76. ©2016 AACR.

  5. Electrostatic endothelial cell seeding technique for small-diameter (<6 mm) vascular prostheses: feasibility testing.

    Science.gov (United States)

    Bowlin, G L; Rittgers, S E

    1997-01-01

    Multiple studies have indicated the importance of surface charge in the adhesion of multiple cardiovascular cell lines including platelets and endothelial cells on the substrate materials (1,4,7-10,12-15). It is the purpose of this article to report a feasibility study conducted using an electrostatic endothelial cell seeding technique. The feasibility study was conducted using human umbilical vein endothelial cells (HUVEC), a static pool apparatus, a voltage source, and a parallel plate capacitor. The HUVEC concentration and seeding times were constant at 560,000 HUVEC/ml and 30 min, respectively. Scanning electron microscopy examination of the endothelial cell adhesion indicated that an induced temporary positive surface charge on e-PTFE graft material enhances the number and the maturation (flattening) of HUVECs adhered. The results indicated that the total number of endothelial cells adhered (70.9 mm2) was increased from 9198 +/- 1194 HUVECs on the control (no induced surface charge) e-PTFE to 22,482 +/- 4814 HUVECs (2.4 x control) on the maximum induced positive surface charge. The total number of cells in the flattened phase of adhesion increased from 837 +/- 275 to 6785 +/- 1012 HUVECs (8.1x) under identical conditions. Thus, the results of the feasibility study support the premise that electrostatic interaction is an important factor in both the endothelial cell adhesion and spreading processes and suggest that the electrostatic seeding technique may lead to an increased patency of small diameter (<6 mm) vascular prostheses.

  6. Vascular progenitor cells isolated from human embryonic stem cells give rise to endothelial and smooth muscle like cells and form vascular networks in vivo.

    Science.gov (United States)

    Ferreira, Lino S; Gerecht, Sharon; Shieh, Hester F; Watson, Nicki; Rupnick, Maria A; Dallabrida, Susan M; Vunjak-Novakovic, Gordana; Langer, Robert

    2007-08-03

    We report that human embryonic stem cells contain a population of vascular progenitor cells that have the ability to differentiate into endothelial-like and smooth muscle (SM)-like cells. Vascular progenitor cells were isolated from EBs grown in suspension for 10 days and were characterized by expression of the endothelial/hematopoietic marker CD34 (CD34+ cells). When these cells are subsequently cultured in EGM-2 (endothelial growth medium) supplemented with vascular endothelial growth factor-165 (50 ng/mL), they give rise to endothelial-like cells characterized by a cobblestone cell morphology, expression of endothelial markers (platelet endothelial cell-adhesion molecule-1, CD34, KDR/Flk-1, vascular endothelial cadherin, von Willebrand factor), incorporation of acetylated low-density lipoprotein, and formation of capillary-like structures when placed in Matrigel. In contrast, when CD34+ cells are cultured in EGM-2 supplemented with platelet-derived growth factor-BB (50 ng/mL), they give rise to SM-like cells characterized by spindle-shape morphology, expression of SM cell markers (alpha-SM actin, SM myosin heavy chain, calponin, caldesmon, SM alpha-22), and the ability to contract and relax in response to common pharmacological agents such as carbachol and atropine but rarely form capillary-like structures when placed in Matrigel. Implantation studies in nude mice show that both cell types contribute to the formation of human microvasculature. Some microvessels contained mouse blood cells, which indicates functional integration with host vasculature. Therefore, the vascular progenitors isolated from human embryonic stem cells using methods established in the present study could provide a means to examine the mechanisms of endothelial and SM cell development, and they could also provide a potential source of cells for vascular tissue engineering.

  7. Cerebral ischemia upregulates vascular endothelin ET(B) receptors in rat

    DEFF Research Database (Denmark)

    Stenman, Emelie; Malmsjö, Malin; Uddman, Erik;

    2002-01-01

    BACKGROUND AND PURPOSE: Elevated levels of endothelin-1 (ET-1) have been reported in cerebral ischemia. A role for ET may prove more important if the vascular receptors were changed. We addressed whether there is any change in ET receptor expression in cerebral ischemia. METHODS: The right middle...... receptors in the pathogenesis of a vascular component after cerebral ischemia....... cerebral artery (MCA) was occluded in male Wistar rats for 2 hours with the intraluminal filament method. The basilar artery and both MCAs were removed after 46 hours of recirculation. The contractile responses to ET-1, a combined ET(A) and ET(B) receptor agonist, and sarafotoxin 6c (S6c), a selective ET...

  8. Cerebral vascular control and metabolism in heat stress

    DEFF Research Database (Denmark)

    Bain, Anthony R; Nybo, Lars; Ainslie, Philip N

    2015-01-01

    implications and pathologies known to confound cerebral functioning during hyperthermia. A reduction in cerebral blood flow (CBF), derived primarily from a respiratory-induced alkalosis, underscores the cerebrovascular changes to hyperthermia. Arterial pressures may also become compromised because of reduced...... is in turn the primary mechanism for impaired tolerance to orthostatic challenges. Any reduction in CBF attenuates the brain's convective heat loss, while the hyperthermic-induced increase in metabolic rate increases the cerebral heat gain. This paradoxical uncoupling of CBF to metabolism increases brain...

  9. Vascular endothelial growth factor signaling is necessary for expansion of medullary microvessels during postnatal kidney development

    DEFF Research Database (Denmark)

    Robdrup Tinning, Anne; Jensen, Boye L; Johnsen, Iben

    2016-01-01

    . In human fetal kidney tissue, immature vascular bundles appeared early in the third trimester (GA27-28) and expanded in size until term. Rat pups treated with the VEGF receptor-2 (VEGFR2) inhibitor vandetanib (100 mg·kg(-1)·day(-1)) from P7 to P12 or P10 to P16 displayed growth retardation and proteinuria......Postnatal inhibition or deletion of angiotensin II (ANG II) AT1 receptors impairs renal medullary mircrovascular development through a mechanism that may include vascular endothelial growth factor (VEGF). The present study was designed to test if VEGF/VEGF receptor signaling is necessary...... mechanism....

  10. Trans fatty acids induce vascular inflammation and reduce vascular nitric oxide production in endothelial cells.

    Directory of Open Access Journals (Sweden)

    Naomi G Iwata

    Full Text Available Intake of trans fatty acids (TFA, which are consumed by eating foods made from partially hydrogenated vegetable oils, is associated with a higher risk of cardiovascular disease. This relation can be explained by many factors including TFA's negative effect on endothelial function and reduced nitric oxide (NO bioavailability. In this study we investigated the effects of three different TFA (2 common isomers of C18 found in partially hydrogenated vegetable oil and a C18 isomer found from ruminant-derived-dairy products and meat on endothelial NF-κB activation and nitric oxide (NO production. Human endothelial cells were treated with increasing concentrations of Elaidic (trans-C18:1 (9 trans, Linoelaidic (trans-C18:2 (9 trans, 12 trans, and Transvaccenic (trans-C18:1 (11 trans for 3 h. Both Elaidic and Linoelaidic acids were associated with increasing NF-κB activation as measured by IL-6 levels and phosphorylation of IκBα, and impairment of endothelial insulin signaling and NO production, whereas Transvaccenic acid was not associated with these responses. We also measured superoxide production, which has been hypothesized to be necessary in fatty acid-dependent activation of NF-κB. Both Elaidic acid and Linoelaidic acid are associated with increased superoxide production, whereas Transvaccenic acid (which did not induce inflammatory responses did not increase superoxide production. We observed differential activation of endothelial superoxide production, NF-κB activation, and reduction in NO production by different C18 isomers suggesting that the location and number of trans double bonds effect endothelial NF-κB activation.

  11. A novel adipocytokine, chemerin exerts anti-inflammatory roles in human vascular endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Yamawaki, Hideyuki, E-mail: yamawaki@vmas.kitasato-u.ac.jp [Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Aomori 034-8628 (Japan); Kameshima, Satoshi; Usui, Tatsuya; Okada, Muneyoshi; Hara, Yukio [Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Aomori 034-8628 (Japan)

    2012-06-22

    Highlights: Black-Right-Pointing-Pointer Chemerin is a novel adipocytokine with almost unknown function in vasculature. Black-Right-Pointing-Pointer Chemerin activates Akt/eNOS/NO pathways in endothelial cells. Black-Right-Pointing-Pointer Chemerin inhibits TNF-{alpha}-induced monocyte adhesion to endothelial cells. Black-Right-Pointing-Pointer Chemerin inhibits TNF-induced VCAM-1 via suppressing NF-{kappa}B and p38 signal. Black-Right-Pointing-Pointer Chemerin is anti-inflammatory through producing NO in vascular endothelium. -- Abstract: Chemerin is a recently identified adipocytokine which plays a role on inflammation and adipocytes metabolism. However, its function in vasculature is largely unknown. We examined the effects of chemerin on vascular endothelial inflammatory states. Treatment of human umbilical vein endothelial cells with chemerin (300 ng/ml, 20 min) induced phosphorylation of Akt (Ser473) and endothelial nitric oxide (NO) synthase (eNOS) (Ser1177). Consistently, chemerin increased intracellular cyclic GMP content. Pretreatment with chemerin (1-300 ng/ml, 24 h) significantly inhibited phosphorylation of nuclear factor (NF)-{kappa}B p65 (Ser536) and p38 as well as vascular cell adhesion molecule (VCAM)-1 expression induced by tumor necrosis factor (TNF)-{alpha} (5 ng/ml, 20 min-6 h). Inhibitor of NF-{kappa}B or p38 significantly inhibited the TNF-{alpha}-induced VCAM-1 expression. Chemerin also inhibited TNF-{alpha}-induced VCAM-1 expression in rat isolated aorta. Moreover, chemerin significantly inhibited monocytes adhesion to TNF-{alpha}-stimulated endothelial cells. The inhibitory effect of chemerin on TNF-{alpha}-induced VCAM-1 was reversed by a NOS inhibitor. Conversely, an NO donor, sodium nitroprusside significantly inhibited TNF-{alpha}-induced VCAM-1. The present results for the first time demonstrate that chemerin plays anti-inflammatory roles by preventing TNF-{alpha}-induced VCAM-1 expression and monocytes adhesion in vascular

  12. The relationship between serum vascular endothelial growth factor A and microsatellite instability in colorectal cancer

    DEFF Research Database (Denmark)

    Hansen, T F; Jensen, L H; Spindler, K-L G;

    2011-01-01

    AIM: It has been suggested that colorectal neoplasms with or without microsatellite instability (MSI) can stimulate angiogenesis in different ways. The vascular endothelial growth factor (VEGF) system is essential for the angiogenetic process and the growth of malignant tumours. The aim of this s......AIM: It has been suggested that colorectal neoplasms with or without microsatellite instability (MSI) can stimulate angiogenesis in different ways. The vascular endothelial growth factor (VEGF) system is essential for the angiogenetic process and the growth of malignant tumours. The aim...... lacking protein expression of any of the four mismatch repair genes (MLH1, PMS2, MSH2 or MSH6) were labelled as high MSI. The rest were considered to be microsatellite stable (MSS). The serum VEGF-A analyses were performed by ELISA. RESULTS: The tumours of 15 patients in the test cohort and 27...

  13. LOW ENDOPHTHALMITIS RATES AFTER INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR INJECTIONS IN AN OPERATION ROOM

    DEFF Research Database (Denmark)

    Freiberg, Florentina J; Brynskov, Troels; Munk, Marion R

    2017-01-01

    PURPOSE: To evaluate the rate of presumed endophthalmitis (EO) after intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections in three European hospitals performed in an operation room (OR) under sterile conditions. METHODS: A retrospective multicenter study between 2003 and 2016...... at three European sites, City Hospital Triemli Zurich, Switzerland (CHT), Zealand University Hospital Roskilde, Denmark (ZUH) and University Clinic Bern, Switzerland (UCB). Intravitreal injection (IVI) database of each department was reviewed. All anti-vascular endothelial growth factor injections were.......0074% per injection (95% CI: 0.0070-0.0078%). Positive cultures were found in 4 out of 10 presumed endophthalmitis cases. CONCLUSION: The standardized sterile technique in an operation room with laminar airflow showed very low rates of endophthalmitis at three European sites....

  14. Arachidonic metabolism and radiation toxicity in cultures of vascular endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Eldor, A.; Vlodavsky, I.; Fuks, Z.; Matzner, Y.; Rubin, D.B. (Hadassah Univ. Hospital, Jerusalem (Israel) Rush-Presbyterian-St. Luke' s Medical Center, Chicago, IL (USA))

    1989-06-01

    The authors conclude that the observed changes in eicosanoid production by vascular endothelial cells exposed to ionizing irradiation may be relevant to the pathogenesis of post-radiation injury in small and large blood vessels. Anomalies of PGI{sub 2} production may lead to thrombosis and accelerated arteriosclerosis which are observed in irradiated vessels. The generation of potent cells may greatly facilitate inflammation in irradiated vessels. The model of irradiated cultured endothelial cells may also be useful for the study of various methods and agents aimed at reducing the radiation induced damage to blood vessels. Evaluation of the capacity of cultured endothelial cells to produce eicosanoids may serve as an appropriate index for the metabolic damage induced by radiation. (author).

  15. Construction and analysis of SSH cDNA library of human vascular endothelial cells related to gastrocarcinoma

    OpenAIRE

    2003-01-01

    AIM: To construct subtracted cDNA libraries of human vascular endothelial cells (VECs) related to gastrocarcinoma using suppression substractive hybridization (SSH) and to analyze cDNA libraries of gastrocarcinoma and VECs in Cancer Gene Anatomy Project (CGAP) database.

  16. Endothelial mechanotransduction proteins and vascular function are altered by dietary sucrose supplementation in healthy young male subjects

    DEFF Research Database (Denmark)

    Gliemann, Lasse; Rytter, Nicolai; Lindskrog, Mads

    2017-01-01

    Endothelial mechanotransduction is important for vascular function but alterations and activation of vascular mechanosensory proteins have not been investigated in humans. In endothelial cell culture, simple sugars effectively impair mechanosensor proteins. To study mechanosensor- and vascular...... function in humans, twelve young healthy male subjects supplemented their diet with 3 × 75 g sucrose day(-1) for 14 days in a randomized cross-over design. Before and after the intervention period, the hyperemic response to passive lower leg movement and active knee extensor exercise was determined...... %) and to 12 watts of active exercise (by 9 ± 1 %), indicating impaired vascular function. Reduced flow response to passive and active exercise was paralleled by a significant upregulation of Platelet endothelial cell adhesion molecule (PECAM-1), endothelial nitric oxide synthase, NADPH oxidase and the Rho...

  17. Pretreatment with recombinant human vascular endothelial growth factor virus replication and inflammation in a perinatal lamb model of RSV infection

    Science.gov (United States)

    Vascular endothelial growth factor (VEGF) is increasingly recognized as a perinatal regulator of lung maturation and surfactant protein expression. Innate immune components including surfactant proteins A and D, and beta defensins have putative antimicrobial activity against pulmonary pathogens inc...

  18. Acidente vascular cerebral ou doença encéfalo vascular ?: Revendo a designação e respeitando a anatomia

    Directory of Open Access Journals (Sweden)

    João Eliézer Ferri-de-Barros

    1994-06-01

    Full Text Available Desde que a doença vascular que acomete o sistema nervoso central de localização intracraniana pode comprometer estruturas supra ou/e infratentoriais, propomos a mudança de "Acidente vascular cerebral" para "Doença encéfalo vascular".

  19. Acidente vascular cerebral ou doença encéfalo vascular ?: Revendo a designação e respeitando a anatomia

    OpenAIRE

    1994-01-01

    Desde que a doença vascular que acomete o sistema nervoso central de localização intracraniana pode comprometer estruturas supra ou/e infratentoriais, propomos a mudança de "Acidente vascular cerebral" para "Doença encéfalo vascular".

  20. Discovery and functional assessment of gene variants in the vascular endothelial growth factor pathway

    OpenAIRE

    Paré-Brunet, Laia; Glubb, Dylan; Evans, Patrick; Berenguer-Llergo, Antoni; Etheridge, Amy S.; Skol, Andrew D.; Di Rienzo, Anna; Duan, Shiwei; Gamazon, Eric R.; Innocenti, Federico

    2013-01-01

    Angiogenesis is a host-mediated mechanism in disease pathophysiology. The vascular endothelial growth factor (VEGF) pathway is a major determinant of angiogenesis, and a comprehensive annotation of the functional variation in this pathway is essential to understand the genetic basis of angiogenesis-related diseases. We assessed the allelic heterogeneity of gene expression, population specificity of cis expression quantitative trait loci (eQTLs), and eQTL function in luciferase assays in CEU a...

  1. Platelet and endothelial adhesion on fluorosurfactant polymers designed for vascular graft modification

    OpenAIRE

    Tang, Chad; Kligman, Faina; Larsen, Coby C.; KOTTKE-MARCHANT, KANDICE; Marchant, Roger E.

    2009-01-01

    A prominent failure mechanism of small-diameter expanded polytetrafluoroethylene (ePTFE) vascular grafts is platelet-mediated thrombosis. We have designed surface modification for ePTFE consisting of a self-assembling fluorosurfactant polymer (FSP) bearing biologically active ligands, including adhesive peptides and polysaccharide moieties. The goal of this biomimetic construct is to improve graft hemocompatibility by promoting rapid surface endothelialization, while minimizing platelet adhes...

  2. Human Vascular Endothelial Growth Factor cDNA Cloning and Expression in Osteoblasts

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Human vascular endothelial growth factor (VEGF) cDNA was amplified by nested polymerase chain reaction method from the HL60 cells. Then a pCD-hVEGF165 recombinant plasmid was constructed. Rabbit osteoblasts were transfected with pCD-hVEGF165 plasmid by lipofectin mediated gene transfer. The transient expressive results were detected by immunohistochemical method. It was observed that the expression of human VEGF gene was detected 72 h after transfecting distinctly.

  3. Differential effects of Bartonella henselae on human and feline macro- and micro-vascular endothelial cells.

    Science.gov (United States)

    Berrich, Moez; Kieda, Claudine; Grillon, Catherine; Monteil, Martine; Lamerant, Nathalie; Gavard, Julie; Boulouis, Henri Jean; Haddad, Nadia

    2011-01-01

    Bartonella henselae, a zoonotic agent, induces tumors of endothelial cells (ECs), namely bacillary angiomatosis and peliosis in immunosuppressed humans but not in cats. In vitro studies on ECs represent to date the only way to explore the interactions between Bartonella henselae and vascular endothelium. However, no comparative study of the interactions between Bartonella henselae and human (incidental host) ECs vs feline (reservoir host) ECs has been carried out because of the absence of any available feline endothelial cell lines.To this purpose, we have developed nine feline EC lines which allowed comparing the effects of Bartonella strains on human and feline micro-vascular ECs representative of the infection development sites such as skin, versus macro-vascular ECs, such as umbilical vein.Our model revealed intrinsic differences between human (Human Skin Microvascular ECs -HSkMEC and Human Umbilical Vein ECs - iHUVEC) and feline ECs susceptibility to Bartonella henselae infection.While no effect was observed on the feline ECs upon Bartonella henselae infection, the human ones displayed accelerated angiogenesis and wound healing.Noticeable differences were demonstrated between human micro- and macro-vasculature derived ECs both in terms of pseudo-tube formation and healing. Interestingly, Bartonella henselae effects on human ECs were also elicited by soluble factors.Neither Bartonella henselae-infected Human Skin Microvascular ECs clinically involved in bacillary angiomatosis, nor feline ECs increased cAMP production, as opposed to HUVEC.Bartonella henselae could stimulate the activation of Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) in homologous cellular systems and trigger VEGF production by HSkMECs only, but not iHUVEC or any feline ECs tested.These results may explain the decreased pathogenic potential of Bartonella henselae infection for cats as compared to humans and strongly suggest that an autocrine secretion of VEGF by human skin

  4. Differential effects of Bartonella henselae on human and feline macro- and micro-vascular endothelial cells

    OpenAIRE

    Berrich, Moez; Kieda, Claudine; Grillon, Catherine; Monteil, Martine; Lamerant, Nathalie; Gavard, Julie; Haddad, Nadia

    2011-01-01

    Bartonella henselae, a zoonotic agent, induces tumors of endothelial cells (ECs), namely bacillary angiomatosis and peliosis in immunosuppressed humans but not in cats. In vitro studies on ECs represent to date the only way to explore the interactions between Bartonella henselae and vascular endothelium. However, no comparative study of the interactions between Bartonella henselae and human (incidental host) ECs vs feline (reservoir host) ECs has been carried out because of the absence of ...

  5. Differential Effects of Bartonella henselae on Human and Feline Macro- and Micro-Vascular Endothelial Cells

    OpenAIRE

    Moez Berrich; Claudine Kieda; Catherine Grillon; Martine Monteil; Nathalie Lamerant; Julie Gavard; Henri Jean Boulouis; Nadia Haddad

    2011-01-01

    Bartonella henselae, a zoonotic agent, induces tumors of endothelial cells (ECs), namely bacillary angiomatosis and peliosis in immunosuppressed humans but not in cats. In vitro studies on ECs represent to date the only way to explore the interactions between Bartonella henselae and vascular endothelium. However, no comparative study of the interactions between Bartonella henselae and human (incidental host) ECs vs feline (reservoir host) ECs has been carried out because of the absence of any...

  6. Differential effects of Bartonella henselae on human and feline macro- and micro-vascular endothelial cells.

    Directory of Open Access Journals (Sweden)

    Moez Berrich

    Full Text Available Bartonella henselae, a zoonotic agent, induces tumors of endothelial cells (ECs, namely bacillary angiomatosis and peliosis in immunosuppressed humans but not in cats. In vitro studies on ECs represent to date the only way to explore the interactions between Bartonella henselae and vascular endothelium. However, no comparative study of the interactions between Bartonella henselae and human (incidental host ECs vs feline (reservoir host ECs has been carried out because of the absence of any available feline endothelial cell lines.To this purpose, we have developed nine feline EC lines which allowed comparing the effects of Bartonella strains on human and feline micro-vascular ECs representative of the infection development sites such as skin, versus macro-vascular ECs, such as umbilical vein.Our model revealed intrinsic differences between human (Human Skin Microvascular ECs -HSkMEC and Human Umbilical Vein ECs - iHUVEC and feline ECs susceptibility to Bartonella henselae infection.While no effect was observed on the feline ECs upon Bartonella henselae infection, the human ones displayed accelerated angiogenesis and wound healing.Noticeable differences were demonstrated between human micro- and macro-vasculature derived ECs both in terms of pseudo-tube formation and healing. Interestingly, Bartonella henselae effects on human ECs were also elicited by soluble factors.Neither Bartonella henselae-infected Human Skin Microvascular ECs clinically involved in bacillary angiomatosis, nor feline ECs increased cAMP production, as opposed to HUVEC.Bartonella henselae could stimulate the activation of Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2 in homologous cellular systems and trigger VEGF production by HSkMECs only, but not iHUVEC or any feline ECs tested.These results may explain the decreased pathogenic potential of Bartonella henselae infection for cats as compared to humans and strongly suggest that an autocrine secretion of VEGF by human

  7. Inhibitive effects of anti-oxidative vitamins on mannitol-induced apoptosis of vascular endothelial cells

    OpenAIRE

    Pan, Kai-yu; Shen, Mei-ping; Ye, Zhi-Hong; Dai, Xiao-na; Shang, Shi-qiang

    2006-01-01

    Objective: Study blood vessel injury and gene expression indicating vascular endothelial cell apoptosis induced by mannitol with and without administration of anti-oxidative vitamins. Methods: Healthy rabbits were randomly divided into four groups. Mannitol was injected into the vein of the rabbit ear in each animal. Pre-treatment prior to mannitol injection was performed with normal saline (group B), vitamin C (group C) and vitamin E (group D). Blood vessel injury was assessed under electron...

  8. The Neurorepellent Slit2 Inhibits Postadhesion Stabilization of Monocytes Tethered to Vascular Endothelial Cells.

    Science.gov (United States)

    Mukovozov, Ilya; Huang, Yi-Wei; Zhang, Qiuwang; Liu, Guang Ying; Siu, Allan; Sokolskyy, Yaroslav; Patel, Sajedabanu; Hyduk, Sharon J; Kutryk, Michael J B; Cybulsky, Myron I; Robinson, Lisa A

    2015-10-01

    The secreted neurorepellent Slit2, acting through its transmembrane receptor, Roundabout (Robo)-1, inhibits chemotaxis of varied cell types, including leukocytes, endothelial cells, and vascular smooth muscle cells, toward diverse attractants. The role of Slit2 in regulating the steps involved in recruitment of monocytes in vascular inflammation is not well understood. In this study, we showed that Slit2 inhibited adhesion of monocytic cells to activated human endothelial cells, as well as to immobilized ICAM-1 and VCAM-1. Microfluidic live cell imaging showed that Slit2 inhibited the ability of monocytes tethered to endothelial cells to stabilize their actin-associated anchors and to resist detachment in response to increasing shear forces. Transfection of constitutively active plasmids revealed that Slit2 inhibited postadhesion stabilization of monocytes on endothelial cells by preventing activation of Rac1. We further found that Slit2 inhibited chemotaxis of monocytes toward CXCL12 and CCL2. To determine whether Slit2 and Robo-1 modulate pathologic monocyte recruitment associated with vascular inflammation and cardiovascular disease, we tested PBMC from patients with coronary artery disease. PBMC from these patients had reduced surface levels of Robo-1 compared with healthy age- and sex-matched subjects, and Slit2 failed to inhibit chemotaxis of PBMC of affected patients, but not healthy control subjects, toward CCL2. Furthermore, administration of Slit2 to atherosclerosis-prone LDL receptor-deficient mice inhibited monocyte recruitment to nascent atherosclerotic lesions. These results demonstrate that Slit2 inhibits chemotaxis of monocytes, as well as their ability to stabilize adhesions and resist detachment forces. Slit2 may represent a powerful new tool to inhibit pathologic monocyte recruitment in vascular inflammation and atherosclerosis.

  9. he role of vascular endothelial growth factor in the pathogenesis of lichen planus and psoriasis

    OpenAIRE

    Artemina Е.М.; Shtoda U.М.; Slesarenko N.A.; Bakulev A.L.; Utz S.R.

    2014-01-01

    The goal: to investigate the process of angiogenesis by determining the level of vascular endothelial growth factor (VEGF) in the blood serum of patients with lichen planus (CPL) and psoriasis. Material and Methods. The study included 50 patients with CPL, 62 patients with psoriasis and 36 were in the control group of healthy individuals. All of the participants were to determine the level of VEGF in a blood serum before treatment. Results. Patients with CPL had an increase in the level of VE...

  10. Amiloride Improves Endothelial Function and Reduces Vascular Stiffness in Female Mice Fed a Western Diet

    Directory of Open Access Journals (Sweden)

    Luis A. Martinez-Lemus

    2017-06-01

    Full Text Available Obese premenopausal women lose their sex related cardiovascular disease protection and develop greater arterial stiffening than age matched men. In female mice, we have shown that consumption of a Western diet (WD, high in fat and refined sugars, is associated with endothelial dysfunction and vascular stiffening, which occur via activation of mineralocorticoid receptors and associated increases in epithelial Na+ channel (ENaC activity on endothelial cells (EnNaC. Herein our aim was to determine the effect that reducing EnNaC activity with a very-low-dose of amiloride would have on decreasing endothelial and arterial stiffness in young female mice consuming a WD. To this end, we fed female mice either a WD or control diet and treated them with or without a very-low-dose of the ENaC-inhibitor amiloride (1 mg/kg/day in the drinking water for 20 weeks beginning at 4 weeks of age. Mice consuming a WD were heavier and had greater percent body fat, proteinuria, and aortic stiffness as assessed by pulse-wave velocity than those fed control diet. Treatment with amiloride did not affect body weight, body composition, blood pressure, urinary sodium excretion, or insulin sensitivity, but significantly reduced the development of endothelial and aortic stiffness, aortic fibrosis, aortic oxidative stress, and mesenteric resistance artery EnNaC abundance and proteinuria in WD-fed mice. Amiloride also improved endothelial-dependent vasodilatory responses in the resistance arteries of WD-fed mice. These results indicate that a very-low-dose of amiloride, not affecting blood pressure, is sufficient to improve endothelial function and reduce aortic stiffness in female mice fed a WD, and suggest that EnNaC-inhibition may be sufficient to ameliorate the pathological vascular stiffening effects of WD-induced obesity in females.

  11. SIRT-1 and vascular endothelial dysfunction with ageing in mice and humans.

    Science.gov (United States)

    Donato, Anthony J; Magerko, Katherine A; Lawson, Brooke R; Durrant, Jessica R; Lesniewski, Lisa A; Seals, Douglas R

    2011-09-15

    We tested the hypothesis that reductions in the cellular deacetylase, sirtuin-1 (SIRT-1), contribute to vascular endothelial dysfunction with ageing via modulation of endothelial nitric oxide synthase (eNOS) acetylation/activation-associated nitric oxide (NO) production. In older (30 months, n = 14) vs. young (5-7 months, n = 16) B6D2F1 mice, aortic protein expression of SIRT-1 and eNOS phosphorylated at serine 1177 were lower (both P SIRT-1 inhibitor, reduced EDD in both young and older mice, abolishing age-related differences, whereas co-administration with l-NAME, an eNOS inhibitor, further reduced EDD similarly in both groups. Endothelium-independent dilatation to sodium nitroprusside (EID), was not altered by age or sirtinol treatment. In older (64 ± 1 years, n = 22) vs. young (25 ± 1 years, n = 16) healthy humans, ACh-induced forearm EDD was impaired (P = 0.01) and SIRT-1 protein expression was 37% lower in endothelial cells obtained from the brachial artery (P SIRT-1 protein expression (r = 0.44, P SIRT-1 may play an important role in vascular endothelial dysfunction with ageing. SIRT-1 may be a key therapeutic target to treat arterial ageing.

  12. PCB 77 dechlorination products modulate pro-inflammatory events in vascular endothelial cells.

    Science.gov (United States)

    Eske, Katryn; Newsome, Bradley; Han, Sung Gu; Murphy, Margaret; Bhattacharyya, Dibakar; Hennig, Bernhard

    2014-05-01

    Persistent organic pollutants such as polychlorinated biphenyls (PCBs) are associated with detrimental health outcomes including cardiovascular diseases. Remediation of these compounds is a critical component of environmental policy. Although remediation efforts aim to completely remove toxicants, little is known about the effects of potential remediation byproducts. We previously published that Fe/Pd nanoparticles effectively dechlorinate PCB 77 to biphenyl, thus eliminating PCB-induced endothelial dysfunction using primary vascular endothelial cells. Herein, we analyzed the toxic effects of PCB congener mixtures (representative mixtures of commercial PCBs based on previous dechlorination data) produced at multiple time points during the dechlorination of PCB 77 to biphenyl. Compared with pure PCB 77, exposing endothelial cells to lower chlorinated PCB byproducts led to improved cellular viability, decreased superoxide production, and decreased nuclear factor kappa B activation based on duration of remediation. Presence of the parent compound, PCB 77, led to significant increases in mRNA and protein inflammatory marker expression. These data implicate that PCB dechlorination reduces biological toxicity to vascular endothelial cells.

  13. Strategies and techniques to enhance the in situ endothelialization of small-diameter biodegradable polymeric vascular grafts.

    Science.gov (United States)

    Melchiorri, Anthony J; Hibino, Narutoshi; Fisher, John P

    2013-08-01

    Due to the lack of success in small-diameter (strategies have evolved utilizing a tissue-engineering approach. Much of this work has focused on enhancing the endothelialization of these grafts. A healthy, confluent endothelial layer provides dynamic control over homeo-stasis, influencing and preventing thrombosis and smooth muscle cell proliferation that can lead to intimal hyperplasia. Strategies to improve endothelialization of biodegradable polymeric grafts have encompassed both chemical and physical modifications to graft surfaces, many focusing on the recruitment of endothelial and endothelial progenitor cells. This review aims to provide a compilation of current and developing strategies that utilize in situ endothelialization to improve vascular graft outcomes, providing a context for the future directions of vascular tissue-engineering strategies that do not require preprocedural cell seeding.

  14. Bacterial toxins activation of abbreviated urea cycle in porcine cerebral vascular smooth muscle cells.

    Science.gov (United States)

    Mishra, Rajesh G; Tseng, Tzu-Ling; Chen, Mei-Fang; Chen, Po-Yi; Lee, Tony J-F

    2016-12-01

    Nitric oxide (NO) overproduction via induction of inducible nitric oxide synthase (iNOS) is implicated in vasodilatory shock in sepsis, leading to septic encephalopathy and accelerating cerebral ischemic injury. An abbreviated urea-cycle (l-citrulline-l-arginine-NO cycle) has been demonstrated in cerebral perivascular nitrergic nerves and endothelial cells but not in normal cerebral vascular smooth muscle cell (CVSMC). This cycle indicates that argininosuccinate synthase (ASS) catalyzes l-citrulline (l-cit) conversion to form argininosuccinate (AS), and subsequent AS cleavage by argininosuccinate lyase (ASL) forms l-arginine (l-arg), the substrate for NO synthesis. The possibility that ASS enzyme in this cycle was induced in the CVSMC in sepsis was examined. Blood-vessel myography technique was used for measuring porcine isolated basilar arterial tone. NO in cultured CVSMC and in condition mediums were estimated by diaminofluorescein (DAF)-induced fluorescence and Griess reaction, respectively. Immunohistochemical and immunoblotting analyses were used to examine iNOS and ASS induction. l-cit and l-arg, which did not relax endothelium-denuded normal basilar arteries precontracted by U-46619, induced significant vasorelaxation with increased NO production in these arteries and the CVSMCs following 6-hour exposure to 20μg/ml lipopolysaccharide (LPS) or lipoteichoic acid (LTA). Pre-treatment with pyrrolidine dithiocarbamate (PDTC) and salicylate (SAL) (NFκB inhibitors), aminoguanidine (AG, an iNOS inhibitor), and nitro-l-arg (NLA, a non-specific NOS inhibitor) blocked NO synthesis in the CVSMC and attenuated l-cit- and l-arg-induced relaxation of LPS- and LTA-treated arteries. Furthermore, immunohistochemical and immunoblotting studies demonstrated that expression of basal iNOS and ASS in the smooth muscle cell of arterial segments denuded of endothelium and the cultured CVSMCs was significantly increased following 6-hour incubation with LPS or LTA. This increased i

  15. Detection of histidine decarboxylase mRNA in human vascular smooth muscle and endothelial cells.

    Science.gov (United States)

    Tippens, A S; Gruetter, C A

    2004-06-01

    The objective of this study was to investigate histamine synthesis capability of human vascular smooth muscle and endothelial cells by detecting histidine decarboxylase (HDC) mRNA. HDC catalyzes exclusively the formation of histamine in mammalian cells. Experiments utilizing nested reverse transcription-polymerase chain reaction (nRT-PCR) were conducted to detect the presence of HDC mRNA. Human aortic smooth muscle cells (HAoSMC) and human aortic endothelial cells (HAEC) were cultured and RNA was extracted and amplified using two sets of HDC-specific primers. Rat liver and kidney RNA were isolated and amplified to serve as positive and negative controls, respectively. Gel electrophoresis of HAoSMC, HAEC and liver mRNA revealed bands coinciding with an expected product size of 440 base pairs. Sequence analysis revealed that the observed bands were the appropriate HDC amplicons. These findings are the first to indicate the presence of HDC mRNA in vascular smooth muscle cells and confirm the presence of HDC mRNA in endothelial cells which is consistent with an ability of these cell types to synthesize histamine in the vascular wall.

  16. [Influence of n-hexane on vascular endothelial active substances in brain tissue in mice].

    Science.gov (United States)

    Lin, L; Zhang, Z Q; Zhang, C Z

    2017-01-20

    Objective: To investigate the influence of n-hexane on vascular endothelial active substances in brain tissue in mice and its significance. Methods: A total of 48 healthy Kunming mice were randomly divided into high-dose exposure group, middle-dose exposure group, low-dose exposure group, and control group, with 12 mice in each group. All groups except the control group were exposed to n-hexane via static inhalation (0.035 g/L, 0.018 g/L, and 0.009 g/L for the high-, middle-, and low-dose exposure groups, respectively) 4 hours a day for 21 days. the mice in the control groups were not exposed to n-hexane. After the exposure, the lev-els of endothelin-1 (ET-1) , nitric oxide (NO) , and angiotensin II (Ang II) in brain tissue were measured in all groups. Results: There were significant differences in the levels of ET-1, NO, and Ang II between the three ex-posure groups and the control group (PHexane can affect the vascular endothe-lial active substances in brain tissue in mice, and the changes and imbalance in vascular endothelial active sub-stances may be one of the reasons for central nervous system impairment caused by n-hexane.

  17. Characterization of ionizing radiation-induced unfolded protein response in human vascular endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Eun Ju; Lee, Yoon Jin; Kang, Seong Man [Laboratory of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2013-04-15

    Misfolded or unfolded proteins within the endoplasmic reticulum (ER stress), viral infection, or amino acid deprivation induce eukaryotic translation initiation factor 2α phosphorylation (eIF2α) in eukaryotic cells, repressing global protein synthesis coincident with preferential translation of activating transcription factor 4 (ATF4). ATF4 is a transcriptional activator of genes involved in amino acid metabolism, cellular redox homeostasis, and regulation of apoptosis. When the eIF2α/ATF4 pathway is initiated by ER stress, the pathway is referred toas the unfolded protein response (UPR). In addition to DNA, proteins may be initial and important targets of ionizing radiation (IR), and the damaged protein can trigger ER stress pathway. Recent investigations suggested that IR induces ER stress followed by UPR in various cell types including intestinal epithelial cells. We conducted this study to determine whether IR can activate UPR in human vascular endothelial cells. Our data have shown that IR increased PERK-dependent eIF2α phosphorylation accompanied by induction in ATF4 protein levels in human vascular endothelial cells without alterations in expressions of XBP-1s and GRP78. Based on these data, we suggest that IR selectively activates PERK branch of unfolded protein response in human vascular endothelial cells.

  18. Microvesicles from the plasma of elderly subjects and from senescent endothelial cells promote vascular calcification

    Science.gov (United States)

    Bodega, Guillermo; Noci, María Victoria; Troyano, Nuria; Bohórquez, Lourdes; Luna, Carlos; Luque, Rafael; Carmona, Andrés; Carracedo, Julia; Ramírez, Rafael

    2017-01-01

    Vascular calcification is commonly seen in elderly people, though it can also appear in middle-aged subjects affected by premature vascular aging. The aim of this work is to test the involvement of microvesicles (MVs) produced by senescent endothelial cells (EC) and from plasma of elderly people in vascular calcification. The present work shows that MVs produced by senescent cultured ECs, plus those found in the plasma of elderly subjects, promote calcification in vascular smooth muscle cells. Only MVs from senescent ECs, and from elderly subjects' plasma, induced calcification. This ability correlated with these types of MVs' carriage of: a) increased quantities of annexins (which might act as nucleation sites for calcification), b) increased quantities of bone-morphogenic protein, and c) larger Ca contents. The MVs of senescent, cultured ECs, and those present in the plasma of elderly subjects, promote vascular calcification. The present results provide mechanistic insights into the observed increase in vascular calcification-related diseases in the elderly, and in younger patients with premature vascular aging, paving the way towards novel therapeutic strategies. PMID:28278131

  19. Estimation of cerebral vascular tone during exercise; evaluation by critical closing pressure in humans

    DEFF Research Database (Denmark)

    Ogoh, Shigehiko; Brothers, R Matthew; Jeschke, Monica;

    2010-01-01

    The aim of the present study was to calculate critical closing pressure (CCP) of the cerebral vasculature at rest and during exercise to estimate cerebral vascular tone. Five men and two women were seated upright for 15 min and then performed 15 min of right-legged knee extension exercise at 40, 60...... and 75% of their maximal workload (WL(max)). Middle cerebral artery blood velocity (MCA V) and blood pressure in the radial artery were recorded. The CCP was calculated by linear extrapolation from 1 min recordings of pairs of systolic and diastolic pressure and MCA V waveforms from both the right...

  20. Applying gold nanoparticles as tumor-vascular disrupting agents during brachytherapy: estimation of endothelial dose enhancement

    Energy Technology Data Exchange (ETDEWEB)

    Ngwa, Wilfred; Makrigiorgos, G Mike; Berbeco, Ross I, E-mail: mmakrigiorgos@lroc.harvard.ed [Department of Radiation Oncology, Division of Medical Physics and Biophysics, Brigham and Women' s Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115 (United States)

    2010-11-07

    Tumor vascular disrupting agents (VDAs) represent a promising approach to the treatment of cancer, in view of the tumor vasculature's pivotal role in tumor survival, growth and metastasis. VDAs targeting the tumor's dysmorphic endothelial cells can cause selective and rapid occlusion of the tumor vasculature, leading to tumor cell death from ischemia and extensive hemorrhagic necrosis. In this study, the potential for applying gold nanoparticles (AuNPs) as VDAs, during brachytherapy, is examined. Analytic calculations based on the electron energy loss formula of Cole were carried out to estimate the endothelial dose enhancement caused by radiation-induced photo/Auger electrons originating from AuNPs targeting the tumor endothelium. The endothelial dose enhancement factor (EDEF), representing the ratio of the dose to the endothelium with and without gold nanoparticles was calculated for different AuNP local concentrations, and endothelial cell thicknesses. Four brachytherapy sources were investigated, I-125, Pd-103, Yb-169, as well as 50 kVp x-rays. The results reveal that, even at relatively low intra-vascular AuNP concentrations, ablative dose enhancement to tumor endothelial cells due to photo/Auger electrons from the AuNPs can be achieved. Pd-103 registered the highest EDEF values of 7.4-271.5 for local AuNP concentrations ranging from 7 to 350 mg g{sup -1}, respectively. Over the same concentration range, I-125, 50 kVp and Yb-169 yielded values of 6.4-219.9, 6.3-214.5 and 4.0-99.7, respectively. Calculations of the EDEF as a function of endothelial cell thickness showed that lower energy sources like Pd-103 reach the maximum EDEF at smaller thicknesses. The results also reveal that the highest contribution to the EDEF comes from Auger electrons, apparently due to their shorter range. Overall, the data suggest that ablative dose enhancement to tumor endothelial cells can be achieved by applying tumor vasculature-targeted AuNPs as adjuvants to

  1. Fenofibrate attenuates nicotine-induced vascular endothelial dysfunction in the rat.

    Science.gov (United States)

    Chakkarwar, Vishal Arvind

    2011-01-01

    The study has been designed to investigate the effect of fenofibrate on nicotine-induced vascular endothelial dysfunction (VED) in rats. Nicotine (2 mg/kg/day, i.p., 4 weeks) was administered to produce VED in rats. The development of VED was assessed by employing isolated aortic ring preparation and estimating serum and aortic concentration of nitrite/nitrate. Further, the integrity of vascular endothelium was assessed using the scanning electron microscopy of thoracic aorta. The expression of mRNA for p22phox and eNOS was assessed by using reverse transcriptase-polymerase chain reaction. Serum thiobarbituric acid reactive substances concentration (TBARS) and aortic superoxide anion concentration were estimated to assess oxidative stress. Moreover, the serum lipid profile was assessed by estimating serum cholesterol, triglycerides and high density lipoprotein. The administration of nicotine induces VED by increased oxidative stress, altered lipid profile and impaired the integrity of vascular endothelium as assessed in terms of decrease in expression of mRNA for endothelial nitric oxide synthase (eNOS), impairing the integrity of vascular endothelium and subsequently decreasing serum and aortic nitrite/nitrate and attenuating acetylcholine-induced endothelium dependent relaxation. Further, nicotine produced oxidative stress, assessed in terms of increase in serum TBARS and aortic superoxide anion generation and increase in expression of mRNA for p22phox. Nicotine altered the lipid profile by increasing the serum cholesterol, triglycerides and decreasing the high density lipoprotein. However, treatment with fenofibrate (32 mg/kg, p.o.) markedly prevented nicotine-induced VED by decreasing oxidative stress and improving integrity of vascular endothelium, normalising the altered lipid profile, increasing the concentration of serum and aortic nitrite/nitrate, enhancing the acetylcholine-induced endothelium dependent relaxation and decreasing serum TBARS and aortic

  2. The contribution of CXCL12-expressing radial glia cells to neuro-vascular patterning during human cerebral cortex development

    Directory of Open Access Journals (Sweden)

    Mariella eErrede

    2014-10-01

    Full Text Available This study was conducted on human developing brain by laser confocal and transmission electron microscopy to make a detailed analysis of important features of blood-brain barrier microvessels and possible control mechanisms of vessel growth and differentiation during cerebral cortex vascularization. The blood-brain barrier status of cortex microvessels was examined at a defined stage of cortex development, at the end of neuroblast waves of migration and before cortex lamination, with blood-brain barrier-endothelial cell markers, namely tight junction proteins (occludin and claudin-5 and influx and efflux transporters (Glut-1 and P-glycoprotein, the latter supporting evidence for functional effectiveness of the fetal blood-brain barrier. According to the well-known roles of astroglia cells on microvessel growth and differentiation, the early composition of astroglia/endothelial cell relationships was analysed by detecting the appropriate astroglia, endothelial, and pericyte markers. GFAP, chemokine CXCL12, and connexin 43 (Cx43 were utilized as markers of radial glia cells, CD105 (endoglin as a marker of angiogenically activated endothelial cells, and proteoglycan NG2 as a marker of immature pericytes. Immunolabeling for CXCL12 showed the highest level of the ligand in radial glial fibres in contact with the growing cortex microvessels. These specialized contacts, recognizable on both perforating radial vessels and growing collaterals, appeared as CXCL12-reactive en passant, symmetrical and asymmetrical vessel-specific RG fibre swellings. At the highest confocal resolution, these RG varicosities showed a CXCL12-reactive dot-like content whose microvesicular nature was confirmed by ultrastructural observations. A further analysis of radial glial varicosities reveals colocalization of CXCL12 with connexin Cx43, which is possibly implicated in vessel-specific chemokine signalling.

  3. Functional characteristics of coronary vasomotor function following intramyocardial gene therapy with naked DNA encoding for vascular endothelial growth factor 165

    NARCIS (Netherlands)

    Tio, RA; Wijpkema, JS; Tan, ES; Asselbergs, FW; Hospers, GAP; Jessurun, GAJ; Zijlstra, F

    2005-01-01

    Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. VEGF gene therapy improves perfusion of ischemic myocardium in experimental models and possibly in patients with end-stage coronary artery disease. In addition to its proliferative and migratory effect on endothelial cells, it

  4. Mononuclear Phagocyte-Derived Microparticulate Caspase-1 Induces Pulmonary Vascular Endothelial Cell Injury.

    Directory of Open Access Journals (Sweden)

    Srabani Mitra

    Full Text Available Lung endothelial cell apoptosis and injury occurs throughout all stages of acute lung injury (ALI/ARDS and impacts disease progression. Lung endothelial injury has traditionally been focused on the role of neutrophil trafficking to lung vascular integrin receptors induced by proinflammatory cytokine expression. Although much is known about the pathogenesis of cell injury and death in ALI/ARDS, gaps remain in our knowledge; as a result of which there is currently no effective pharmacologic therapy. Enzymes known as caspases are essential for completion of the apoptotic program and secretion of pro-inflammatory cytokines. We hypothesized that caspase-1 may serve as a key regulator of human pulmonary microvascular endothelial cell (HPMVEC apoptosis in ALI/ARDS. Our recent experiments confirm that microparticles released from stimulated monocytic cells (THP1 induce lung endothelial cell apoptosis. Microparticles pretreated with the caspase-1 inhibitor, YVAD, or pan-caspase inhibitor, ZVAD, were unable to induce cell death of HPMVEC, suggesting the role of caspase-1 or its substrate in the induction of HPMVEC cell death. Neither un-induced microparticles (control nor direct treatment with LPS induced apoptosis of HPMVEC. Further experiments showed that caspase-1 uptake into HPMVEC and the induction of HPMVEC apoptosis was facilitated by caspase-1 interactions with microparticulate vesicles. Altering vesicle integrity completely abrogated apoptosis of HPMVEC suggesting an encapsulation requirement for target cell uptake of active caspase-1. Taken together, we confirm that microparticle centered caspase-1 can play a regulator role in endothelial cell injury.

  5. Cord blood-circulating endothelial progenitors for treatment of vascular diseases.

    Science.gov (United States)

    Lavergne, M; Vanneaux, V; Delmau, C; Gluckman, E; Rodde-Astier, I; Larghero, J; Uzan, G

    2011-04-01

    Adult peripheral blood (PB) endothelial progenitor cells (EPC) are produced in the bone marrow and are able to integrate vascular structures in sites of neoangiogenesis. EPCs thus represent a potential therapeutic tool for ischaemic diseases. However, use of autologous EPCs in cell therapy is limited by their rarity in adult PB. Cord blood (CB) contains more EPCs than PB, and they are functional after expansion. They form primary colonies that give rise to secondary colonies, each yielding more than 10(7) cells after few passages. The number of endothelial cells obtained from one unit of CB is compatible with potential clinical application. EPC colonies can be securely produced, expanded and cryopreserved in close culture devices and endothelial cells produced in these conditions are functional as shown in different in vitro and in vivo assays. As CB EPC-derived endothelial cells would be allogeneic to patients, it would be of interest to prepare them from ready-existing CB banks. We show that not all frozen CB units from a CB bank are able to generate EPC colonies in culture, and when they do so, number of colonies is lower than that obtained with fresh CB units. However, endothelial cells derived from frozen CB have the same phenotypical and functional properties than those derived from fresh CB. This indicates that CB cryopreservation should be improved to preserve integrity of stem cells other than haematopoietic ones. Feasibility of using CB for clinical applications will be validated in porcine models of ischaemia.

  6. SNS-032 Prevents Tumor Cell-Induced Angiogenesis By Inhibiting Vascular Endothelial Growth Factor

    Directory of Open Access Journals (Sweden)

    M. Aktar Ali

    2007-05-01

    Full Text Available Cell proliferation, migration, and capillary network formation of endothelial cells are the fundamental steps for angiogenesis, which involves the formation of new blood vessels. The purpose of this study is to investigate the effect of a novel aminothiazole SNS-032 on these critical steps for in vitro angiogenesis using a coculture system consisting of human umbilical vein endothelial cells (HUVECs and human glioblastoma cells (U87MG. SNS-032 is a potent selective inhibitor of cyclin-dependent kinases 2, 7, and 9, and inhibits both transcription and cell cycle. In this study, we examined the proliferation and viability of HUVECs and U87MG cells in the presence of SNS-032 and observed a dose-dependent inhibition of cellular proliferation in both cell lines. SNS-032 inhibited threedimensional capillary network formations of endothelial cells. In a coculture study, SNS-032 completely prevented U87MG cell-mediated capillary formation of HUVECs. This inhibitor also prevented the migration of HUVECs when cultured alone or cocultured with U87MG cells. In addition, SNS-032 significantly prevented the production of vascular endothelial growth factor (VEGF in both cell lines, whereas SNS-032 was less effective in preventing capillary network formation and migration of endothelial cells when an active recombinant VEGF was added to the medium. In conclusion, SNS-032 prevents in vitro angiogenesis, and this action is attributable to blocking of VEGF.

  7. Astrocyte-derived vascular endothelial growth factor stabilizes vessels in the developing retinal vasculature.

    Directory of Open Access Journals (Sweden)

    Andrew Scott

    Full Text Available Vascular endothelial growth factor (VEGF plays a critical role in normal development as well as retinal vasculature disease. During retinal vascularization, VEGF is most strongly expressed by not yet vascularized retinal astrocytes, but also by retinal astrocytes within the developing vascular plexus, suggesting a role for retinal astrocyte-derived VEGF in angiogenesis and vessel network maturation. To test the role of astrocyte-derived VEGF, we used Cre-lox technology in mice to delete VEGF in retinal astrocytes during development. Surprisingly, this only had a minor impact on retinal vasculature development, with only small decreases in plexus spreading, endothelial cell proliferation and survival observed. In contrast, astrocyte VEGF deletion had more pronounced effects on hyperoxia-induced vaso-obliteration and led to the regression of smooth muscle cell-coated radial arteries and veins, which are usually resistant to the vessel-collapsing effects of hyperoxia. These results suggest that VEGF production from retinal astrocytes is relatively dispensable during development, but performs vessel stabilizing functions in the retinal vasculature and might be relevant for retinopathy of prematurity in humans.

  8. Effect of ruthenium red, a ryanodine receptor antagonist in experimental diabetes induced vascular endothelial dysfunction and associated dementia in rats.

    Science.gov (United States)

    Jain, Swati; Sharma, Bhupesh

    2016-10-01

    Diabetes mellitus is considered as a main risk factor for vascular dementia. In the past, we have reported the induction of vascular dementia by experimental diabetes. This study investigates the efficacy of a ruthenium red, a ryanodine receptor antagonist and pioglitazone in the pharmacological interdiction of pancreatectomy diabetes (PaD) induced vascular endothelial dysfunction and subsequent vascular dementia in rats. Attentional set shifting and Morris water-maze test were used for assessment of learning and memory. Vascular endothelial function, blood brain barrier permeability, serum glucose, serum nitrite/nitrate, oxidative stress (viz. aortic superoxide anion, brain thiobarbituric acid reactive species and brain glutathione), brain calcium and inflammation (myeloperoxidase) were also estimated. PaD rats have shown impairment of endothelial function, blood brain barrier permeability, learning and memory along with an increase in brain inflammation, oxidative stress and calcium. Administration of ruthenium red and pioglitazone has significantly attenuated PaD induced impairment of learning, memory, blood brain barrier permeability, endothelial function and biochemical parameters. It may be concluded that ruthenium red, a ryanodine receptor antagonist and pioglitazone, a PPAR-γ agonist may be considered as potent pharmacological agent for the management of PaD induced endothelial dysfunction and subsequent vascular dementia. Ryanodine receptor may be explored further for their possible benefits in vascular dementia.

  9. Vascular endothelial growth factor co-ordinates proper development of lung epithelium and vasculature.

    Science.gov (United States)

    Zhao, Liqing; Wang, Ke; Ferrara, Napoleone; Vu, Thiennu H

    2005-07-01

    The vasculature forms an intrinsic functional component of the lung and its development must be tightly regulated and coordinated with lung epithelial morphogenesis. Vascular endothelial growth factor (VEGF) and its receptors are highly expressed in a complementary pattern in the lungs during embryonic development. VEGF is expressed by epithelium and the receptors in the surrounding mesenchyme. To determine the function of VEGF in lung formation, we inhibited its activity using a soluble receptor in lung renal capsule grafts. Inhibition of VEGF results in inhibition of vascular development and significant alteration in epithelial development. Epithelial proliferation is inhibited, sacculation is impaired, and the epithelium undergoes apoptosis. Interestingly, when VEGF is attenuated, epithelial differentiation still proceeds, as shown by acquisition of both proximal and distal markers. These data show that VEGF co-ordinates epithelial and vascular development. It is required for the development of the lung vasculature and the vasculature is necessary for epithelial proliferation and morphogenesis, but not for cell differentiation.

  10. Phylogenetic analysis and positive-selection site detecting of vascular endothelial growth factor family in vertebrates.

    Science.gov (United States)

    He, Wenwu; Tang, Yanyan; Qi, Bin; Lu, Chuansen; Qin, Chao; Wei, Yunfei; Yi, Jiachao; Chen, Mingwu

    2014-02-10

    Vascular endothelial growth factor (VEGF), known to play an important role in vascular homeostasis, vascular integrity and angiogenesis, is little known about the evolutionary relationship of its five members especially the role of gene duplication and natural selection in the evolution of the VEGF family. In this study, seventy-five full-length cDNA sequences from 33 vertebrate species were extracted from the NCBI's GenBank, UniProt protein database and the Ensembl database. By phylogenetic analyses, we investigated the origin, conservation, and evolution of the VEGFs. Five VEGF family members in vertebrates might be formed by gene duplication. The inferred evolutionary transitions that separate members which belong to different gene clusters correlated with changes in functional properties. Selection analysis and protein structure analysis were combined to explain the relationship of the site-specific evolution in the vertebrate VEGF family. Eleven positive selection sites, one transmembrane region and the active sites were detected in this process.

  11. Acute Effect of High-Intensity Eccentric Exercise on Vascular Endothelial Function in Young Men.

    Science.gov (United States)

    Choi, Youngju; Akazawa, Nobuhiko; Zempo-Miyaki, Asako; Ra, Song-Gyu; Shiraki, Hitoshi; Ajisaka, Ryuichi; Maeda, Seiji

    2016-08-01

    Choi, Y, Akazawa, N, Zempo-Miyaki, A, Ra, S-G, Shiraki, H, Ajisaka, R, and Maeda, S. Acute effect of high-intensity eccentric exercise on vascular endothelial function in young men. J Strength Cond Res 30(8): 2279-2285, 2016-Increased central arterial stiffness is as an independent risk factor for cardiovascular disease. Evidence regarding the effects of high-intensity resistance exercise on vascular endothelial function and central arterial stiffness is conflicting. The purpose of this study was to examine the effects of acute high-intensity eccentric exercise on vascular endothelial function and central arterial stiffness. We evaluated the acute changes in endothelium-dependent flow-mediated dilation (FMD), low-flow-mediated constriction (L-FMC), and arterial stiffness after high-intensity eccentric exercise. Seven healthy, sedentary men (age, 24 ± 1 year) performed maximal eccentric elbow flexor exercise using their nondominant arm. Before and 45 minutes after eccentric exercise, carotid arterial compliance and brachial artery FMD and L-FMC in the nonexercised arm were measured. Carotid arterial compliance was significantly decreased, and β-stiffness index significantly increased after eccentric exercise. Brachial FMD was significantly reduced after eccentric exercise, whereas there was no significant difference in brachial L-FMC before and after eccentric exercise. A positive correlation was detected between change in arterial compliance and change in FMD (r = 0.779; p ≤ 0.05), and a negative correlation was detected between change in β-stiffness index and change in FMD (r = -0.891; p eccentric exercise. In this study, acute high-intensity eccentric exercise increased central arterial stiffness; this increase was accompanied by a decrease in endothelial function caused by reduced endothelium-dependent vasodilation but not by a change in endothelium-dependent vasoconstriction.

  12. Matrix metalloproteinase-1 expression by interaction between monocytes and vascular endothelial cells.

    Science.gov (United States)

    Hojo, Y; Ikeda, U; Takahashi, M; Sakata, Y; Takizawa, T; Okada, K; Saito, T; Shimada, K

    2000-08-01

    There is accumulating evidence of complicated interactions among vascular cells, i.e. endothelial cells, smooth muscle cells and monocytes/macrophages, in the regulation of vascular function and remodeling. We have investigated the mechanisms responsible for matrix metalloproteinase (MMP)-1 expression by interactions between monocytes and vascular endothelial cells. THP-1 cells (human monocytic cell line) and human umbilical vein endothelial cells (HUVECs) were cocultured. MMP-1 levels in the culture medium were measured by enzyme-linked immunosorbent assays. Collagenolytic activity in the culture medium was measured by fluorescence labeled-collagen digestion. Immunohistochemistry using an anti-MMP antibody was carried out to determine which types of cell produce MMP-1. The addition of THP-1 cells to HUVECs for 48 h induced increases in MMP-1 levels and collagenolytic activity, which were 5- and 2-fold relative to those of HUVECs alone, respectively. A separate coculture experiment revealed that direct contact of THP-1 cells and HUVECs contributed to enhanced MMP-1 production in the cocolture. Immunohistochemical analysis revealed that both types of cell produce MMP-1 in the coculture. Neutralizing anti-interleukin-1 beta and tumor necrosis factor- alpha antibodies inhibited MMP-1 production by the coculture. The Src kinase and MEK inhibitors significantly inhibited MMP-1 production by the coculture. Coculture of THP-1 cells and HUVECs induced significant increases in Src and mitogen activated protein (MAP) kinase activities. Enhanced MMP-1 expression induced by monocyte-endothelial cell interactions may play an important role in the pathogenesis of atherosclerosis and plaque rupture.

  13. Study of the Dynamics of Transcephalic Cerebral Impedance Data during Cardio-Vascular Surgery

    Science.gov (United States)

    Atefi, S. R.; Seoane, F.; Lindecrantz, K.

    2013-04-01

    Postoperative neurological deficits are one of the risks associated with cardio vascular surgery, necessitating development of new techniques for cerebral monitoring. In this study an experimental observation regarding the dynamics of transcephalic Electrical Bioimpedance (EBI) in patients undergoing cardiac surgery with and without extracorporeal circulation (ECC) was conducted to investigate the potential use of electrical Bioimpedance for cerebral monitoring in cardio vascular surgery. Tetrapolar transcephalic EBI measurements at single frequency of 50 kHz were recorded prior to and during cardio vascular surgery. The obtained results show that the transcephalic impedance decreases in both groups of patients as operation starts, however slight differences in these two groups were also observed with the cerebral impedance reduction in patients having no ECC being less common and not as pronounced as in the ECC group. Changes in the cerebral impedance were in agreement with changes of haematocrit and temperature. The origin of EBI changes is still unexplained however these results encourage us to continue investigating the application of electrical bioimpedance cerebral monitoring clinically.

  14. In Vivo Vascularization of Endothelial Cells Derived from Bone Marrow Mesenchymal Stem Cells in SCID Mouse Model

    Directory of Open Access Journals (Sweden)

    Allameh Abdolamir

    2016-07-01

    Full Text Available Objective In vivo and in vitro stem cell differentiation into endothelial cells is a promising area of research for tissue engineering and cell therapy. Materials and Methods We induced human mesenchymal stem cells (MSCs to differentiate to endothelial cells that had the ability to form capillaries on an extracellular matrix (ECM gel. Thereafter, the differentiated endothelial cells at early stage were characterized by expression of specific markers such as von Willebrand factor (vWF, vascular endothelial growth factor (VEGF receptor 2, and CD31. In this experimental model, the endothelial cells were transplanted into the groins of severe combined immunodeficiency (SCID mice. After 30 days, we obtained tissue biopsies from the transplantation sites. Biopsies were processed for histopathological and double immunohistochemistry (DIHC staining. Results Endothelial cells at the early stage of differentiation expressed endothelial markers. Hematoxylin and eosin (H&E staining, in addition to DIHC demonstrated homing of the endothelial cells that underwent vascularization in the injected site. Conclusion The data clearly showed that endothelial cells at the early stage of differentiation underwent neovascularization in vivo in SCID mice. Endothelial cells at their early stage of differentiation have been proven to be efficient for treatment of diseases with impaired vasculogenesis.

  15. Role of vascular peroxidase 1 in senescence of endothelial cells in diabetes rats.

    Science.gov (United States)

    Liu, Si-Yu; Yuan, Qiong; Li, Xiao-Hui; Hu, Chang-Ping; Hu, Rong; Zhang, Guo-Gang; Li, Dai; Li, Yuan-Jian

    2015-10-15

    Reactive oxygen species (ROS) is thought as a major reason of vascular injury in diabetes. Vascular peroxidase 1 (VPO1) is a newly found peroxidase playing an important role in inducing oxidative stress. In the present experiment, we tested the role of VPO1 in senescence of endothelial cells in streptozotocin (STZ)-induced diabetic rats and cultured endothelial cells. Blood samples were collected from carotid arteries. Vasodilator responses to acetylcholine (Ach) in the isolated aortic rings were measured, serum concentration of glucose, tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) and the expression of VPO1 in the aorta were determined. Endothelial cells were treated with high glucose or H2O2, the concentrations of MCP-1, TNF-α and hypochlorous acid (HOCl) and the expression of VPO1 were determined. shRNA of VPO1 was used for mechanism research in cultured cells. Vasodilator responses to Ach were impaired markedly and the serum concentrations of glucose, TNF-α and MCP-1 were significantly increased in diabetic rats. The expression of VPO1 in the aorta was upregulated in diabetic rats. High glucose treatment significantly decreased cell viability and elevated the levels of MCP-1, TNF-α and HOCl and upregulated the expression of VPO1. H2O2 treatment significantly induced cellular senescence, inhibited eNOS expression and NO production. The effects of high glucose and H2O2 were attenuated by shRNA interference of VPO1. VPO1 plays an important role in senescence of endothelial cells and endothelial dysfunction by induction of oxidative stress and inflammatory reaction in type 2 diabetic rats. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  16. Synergistic effect of angiotensin II on vascular endothelial growth factor-A-mediated differentiation of bone marrow-derived mesenchymal stem cells into endothelial cells

    OpenAIRE

    Ikhapoh, Izuagie Attairu; Pelham, Christopher J; Agrawal, Devendra K.

    2015-01-01

    Introduction Increased levels of angiotensin II (Ang II) and activity of Ang II receptor type 1 (AT1R) elicit detrimental effects in cardiovascular disease. However, the role of Ang II receptor type 2 (AT2R) remains poorly defined. Mesenchymal stem cells (MSCs) replenish and repair endothelial cells in the cardiovascular system. Herein, we investigated a novel role of angiotensin signaling in enhancing vascular endothelial growth factor (VEGF)-A-mediated differentiation of MSCs into endotheli...

  17. Exercise training improves vascular endothelial function in patients with type 1 diabetes.

    Science.gov (United States)

    Fuchsjäger-Mayrl, Gabriele; Pleiner, Johannes; Wiesinger, Günther F; Sieder, Anna E; Quittan, Michael; Nuhr, Martin J; Francesconi, Claudia; Seit, Hans-Peter; Francesconi, Mario; Schmetterer, Leopold; Wolzt, Michael

    2002-10-01

    OBJECTIVE-Impaired endothelial function of resistance and conduit arteries can be detected in patients with type 1 diabetes. We studied whether a persistent improvement of endothelial function can be achieved by regular physical training. RESEARCH DESIGN AND METHODS-The study included 26 patients with type 1 diabetes of 20 +/- 10 years' duration and no overt angiopathy; 18 patients (42 +/- 10 years old) participated in a bicycle exercise training program, and 8 patients with type 1 diabetes (33 +/- 11 years old) served as control subjects. Vascular function of conduit arteries was assessed by flow-mediated and endothelium-independent dilation of the brachial artery and of resistance vessels by the response of ocular fundus pulsation amplitudes to intravenous N(G)-monomethyl-L-arginine (L-NMMA) at baseline, after 2 and 4 months of training, and 8 months after cessation of regular exercise. RESULTS-Training increased peak oxygen uptake (VO(2max)) by 13% after 2 months and by 27% after 4 months (P = 0.04). Flow-mediated dilation (FMD) of the brachial artery increased from 6.5 +/- 1.1 to 9.8 +/- 1.1% (P = 0.04) by training. L-NMMA administration decreased fundus pulsation amplitude (FPA) by 9.1 +/- 0.9% before training and by 13.4 +/- 1.5% after 4 months of training (P = 0.02). VO(2max), FMD, and FPA were unchanged in the control group. Vascular effects from training were abrogated 8 months after cessation of exercise. CONCLUSIONS-Our study demonstrates that aerobic exercise training can improve endothelial function in different vascular beds in patients with long-standing type 1 diabetes, who are at considerable risk for diabetic angiopathy. However, the beneficial effect on vascular function is not maintained in the absence of exercise.

  18. Zinc oxide particles induce inflammatory responses in vascular endothelial cells via NF-{kappa}B signaling

    Energy Technology Data Exchange (ETDEWEB)

    Tsou, Tsui-Chun, E-mail: tctsou@nhri.org.tw [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli County, Taiwan (China); Yeh, Szu-Ching; Tsai, Feng-Yuan; Lin, Ho-Jane [Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Miaoli County, Taiwan (China); Cheng, Tsun-Jen [Institute of Occupational Medicine and Industrial Hygiene, National Taiwan University, Taipei, Taiwan (China); Chao, How-Ran [Department of Environmental Science and Engineering, National Pingtung University of Science and Technology, Neipu, Pingtung, Taiwan (China); Tai, Lin-Ai [Center for Nanomedicine Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan (China)

    2010-11-15

    This study investigated inflammatory effects of zinc oxide (ZnO) particles on vascular endothelial cells. The effects of 50 and 100-nm ZnO particles on human umbilical vein endothelial cells (HUVECs) were characterized by assaying cytotoxicity, cell proliferation, and glutathione levels. A marked drop in survival rate was observed when ZnO concentration was increased to 45 {mu}g/ml. ZnO concentrations of {<=}3 {mu}g/ml resulted in increased cell proliferation, while those of {<=}45 {mu}g/ml caused dose-dependent increases in oxidized glutathione levels. Treatments with ZnO concentrations {<=}45 {mu}g/ml were performed to determine the expression of intercellular adhesion molecule-1 (ICAM-1) protein, an indicator of vascular endothelium inflammation, revealing that ZnO particles induced a dose-dependent increase in ICAM-1 expression and marked increases in NF-{kappa}B reporter activity. Overexpression of I{kappa}B{alpha} completely inhibited ZnO-induced ICAM-1 expression, suggesting NF-{kappa}B plays a pivotal role in regulation of ZnO-induced inflammation in HUVECs. Additionally, TNF-{alpha}, a typical inflammatory cytokine, induced ICAM-1 expression in an NF-{kappa}B-dependent manner, and ZnO synergistically enhanced TNF-{alpha}-induced ICAM-1 expression. Both 50 and 100-nm ZnO particles agglomerated to similar size distributions. This study reveals an important role for ZnO in modulating inflammatory responses of vascular endothelial cells via NF-{kappa}B signaling, which could have important implications for treatments of vascular disease.

  19. Endothelial Cell Migration and Vascular Endothelial Growth Factor Expression Are the Result of Loss of Breast Tissue Polarity

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Amy; Cuevas, Ileana; Kenny, Paraic A; Miyake, Hiroshi; Mace, Kimberley; Ghajar, Cyrus; Boudreau, Aaron; Bissell, Mina; Boudreau, Nancy

    2009-05-26

    Recruiting a new blood supply is a rate-limiting step in tumor progression. In a three-dimensional model of breast carcinogenesis, disorganized, proliferative transformed breast epithelial cells express significantly higher expression of angiogenic genes compared with their polarized, growth-arrested nonmalignant counterparts. Elevated vascular endothelial growth factor (VEGF) secretion by malignant cells enhanced recruitment of endothelial cells (EC) in heterotypic cocultures. Significantly, phenotypic reversion of malignant cells via reexpression of HoxD10, which is lost in malignant progression, significantly attenuated VEGF expression in a hypoxia-inducible factor 1{alpha}-independent fashion and reduced EC migration. This was due primarily to restoring polarity: forced proliferation of polarized, nonmalignant cells did not induce VEGF expression and EC recruitment, whereas disrupting the architecture of growth-arrested, reverted cells did. These data show that disrupting cytostructure activates the angiogenic switch even in the absence of proliferation and/or hypoxia and restoring organization of malignant clusters reduces VEGF expression and EC activation to levels found in quiescent nonmalignant epithelium. These data confirm the importance of tissue architecture and polarity in malignant progression.

  20. Three Cases of Organized Hematoma of the Maxillary Sinus: Clinical Features and Immunohistological Studies for Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor 2 Expressions

    Directory of Open Access Journals (Sweden)

    Shoichiro Imayoshi

    2015-01-01

    Full Text Available Objectives. Organized hematoma (OH is a rare, nonneoplastic, hemorrhagic lesion causing mucosal swelling and bone thinning, mainly in the maxillary sinus. We aimed to clarify the clinical presentation and treatment of OH. Methods. Three cases of maxillary sinus OH and a literature review are presented. Results. Three men aged 16–40 years complained of nasal obstruction, frequent epistaxis, and/or headache. Clinical and radiological examinations revealed a maxillary sinus OH. They were cured in a piecemeal fashion via endoscopic middle meatal antrostomy. Furthermore, vascular endothelial growth factor and its receptor were expressed in the lesion. Conclusions. The pathogenesis of OH is unclear and it presents various histological and imaging findings; however, it is not difficult to rule out malignant tumors. Minimally invasive surgery such as endoscopic sinus surgery can cure it completely. Thus, it is important to determine the diagnosis using CT and MRI and to quickly provide surgical treatment.

  1. In vitro modeling of endothelial interaction with macrophages and pericytes demonstrates Notch signaling function in the vascular microenvironment.

    Science.gov (United States)

    Tattersall, Ian W; Du, Jing; Cong, Zhuangzhuang; Cho, Bennet S; Klein, Alyssa M; Dieck, Chelsea L; Chaudhri, Reyhaan A; Cuervo, Henar; Herts, James H; Kitajewski, Jan

    2016-04-01

    Angiogenesis is regulated by complex interactions between endothelial cells and support cells of the vascular microenvironment, such as tissue myeloid cells and vascular mural cells. Multicellular interactions during angiogenesis are difficult to study in animals and challenging in a reductive setting. We incorporated stromal cells into an established bead-based capillary sprouting assay to develop assays that faithfully reproduce major steps of vessel sprouting and maturation. We observed that macrophages enhance angiogenesis, increasing the number and length of endothelial sprouts, a property we have dubbed "angiotrophism." We found that polarizing macrophages toward a pro-inflammatory profile further increased their angiotrophic stimulation of vessel sprouting, and this increase was dependent on macrophage Notch signaling. To study endothelial/pericyte interactions, we added vascular pericytes directly to the bead-bound endothelial monolayer. These pericytes formed close associations with the endothelial sprouts, causing increased sprout number and vessel caliber. We found that Jagged1 expression and Notch signaling are essential for the growth of both endothelial cells and pericytes and may function in their interaction. We observed that combining endothelial cells with both macrophages and pericytes in the same sprouting assay has multiplicative effects on sprouting. These results significantly improve bead-capillary sprouting assays and provide an enhanced method for modeling interactions between the endothelium and the vascular microenvironment. Achieving this in a reductive in vitro setting represents a significant step toward a better understanding of the cellular elements that contribute to the formation of mature vasculature.

  2. Fibroblast growth factor-2 and vascular endothelial growth factor mediated augmentation of angiogenesis and bone formation in vascularized bone allotransplants.

    Science.gov (United States)

    Larsen, Mikko; Willems, Wouter F; Pelzer, Michael; Friedrich, Patricia F; Dadsetan, Mahrokh; Bishop, Allen T

    2014-05-01

    We previously demonstrated recipient-derived neoangiogenesis to maintain viability of living bone allogeneic transplants without long-term immunosuppression. The effect of cytokine delivery to enhance this process is studied. Vascularized femur transplantation was performed from Dark Agouti to Piebald Virol Glaxo rats. Poly(d,l-lactide-co-glycolide) microspheres loaded with buffer (N = 11), basic fibroblast growth factor (FGF2) (N = 10), vascular endothelial growth factor (VEGF) (N = 11), or both (N = 11) were inserted intramedullarly alongside a recipient-derived arteriovenous bundle. FK-506 was administered for 2 weeks. At 18 weeks, bone blood flow, microangiography, histologic, histomorphometric, and alkaline phosphatase measurements were performed. Bone blood flow was greater in the combined group than control and VEGF groups (P = 0.04). Capillary density was greater in the FGF2 group than in the VEGF and combined groups (P Bone viability, growth, and alkaline phosphatase activity did not vary significantly between groups. Neoangiogenesis in vascularized bone allotransplants is enhanced by angiogenic cytokine delivery, with results using FGF2 that are comparable to isotransplant from previous studies. Further studies are needed to achieve bone formation similar to isotransplants. Copyright © 2013 Wiley Periodicals, Inc.

  3. The rationale and design of the antihypertensives and vascular, endothelial, and cognitive function (AVEC trial in elderly hypertensives with early cognitive impairment: Role of the renin angiotensin system inhibition

    Directory of Open Access Journals (Sweden)

    Hart Meaghan

    2009-11-01

    Full Text Available Abstract Background Prior evidence suggests that the renin angiotensin system and antihypertensives that inhibit this system play a role in cognitive, central vascular, and endothelial function. Our objective is to conduct a double-blind randomized controlled clinical trial, the antihypertensives and vascular, endothelial, and cognitive function (AVEC, to compare 1 year treatment of 3 antihypertensives (lisinopril, candesartan, or hydrochlorothiazide in their effect on memory and executive function, cerebral blood flow, and central endothelial function of seniors with hypertension and early objective evidence of executive or memory impairments. Methods/Design The overall experimental design of the AVEC trial is a 3-arm double blind randomized controlled clinical trial. A total of 100 community eligible individuals (60 years or older with hypertension and early cognitive impairment are being recruited from the greater Boston area and randomized to lisinopril, candesartan, or hydrochlorothiazide ("active control" for 12 months. The goal of the intervention is to achieve blood pressure control defined as SBP 20 and without clinical diagnosis of dementia or Alzheimer's disease. Individuals who are currently receiving antihypertensives are eligible to participate if the participants and the primary care providers are willing to taper their antihypertensives. Participants undergo cognitive assessment, measurements of cerebral blood flow using Transcranial Doppler, and central endothelial function by measuring changes in cerebral blood flow in response to changes in end tidal carbon dioxide at baseline (off antihypertensives, 6, and 12 months. Our outcomes are change in cognitive function score (executive and memory, cerebral blood flow, and carbon dioxide cerebral vasoreactivity. Discussion The AVEC trial is the first study to explore impact of antihypertensives in those who are showing early evidence of cognitive difficulties that did not reach the

  4. Update on vascular endothelial Ca2+ signalling: A tale of ion channels, pumps and transporters

    Science.gov (United States)

    Moccia, Francesco; Berra-Romani, Roberto; Tanzi, Franco

    2012-01-01

    A monolayer of endothelial cells (ECs) lines the lumen of blood vessels and forms a multifunctional transducing organ that mediates a plethora of cardiovascular processes. The activation of ECs from as state of quiescence is, therefore, regarded among the early events leading to the onset and progression of potentially lethal diseases, such as hypertension, myocardial infarction, brain stroke, and tumor. Intracellular Ca2+ signals have long been know to play a central role in the complex network of signaling pathways regulating the endothelial functions. Notably, recent work has outlined how any change in the pattern of expression of endothelial channels, transporters and pumps involved in the modulation of intracellular Ca2+ levels may dramatically affect whole body homeostasis. Vascular ECs may react to both mechanical and chemical stimuli by generating a variety of intracellular Ca2+ signals, ranging from brief, localized Ca2+ pulses to prolonged Ca2+ oscillations engulfing the whole cytoplasm. The well-defined spatiotemporal profile of the subcellular Ca2+ signals elicited in ECs by specific extracellular inputs depends on the interaction between Ca2+ releasing channels, which are located both on the plasma membrane and in a number of intracellular organelles, and Ca2+ removing systems. The present article aims to summarize both the past and recent literature in the field to provide a clear-cut picture of our current knowledge on the molecular nature and the role played by the components of the Ca2+ machinery in vascular ECs under both physiological and pathological conditions. PMID:22905291

  5. Enhanced Viability of Endothelial Colony Forming Cells in Fibrin Microbeads for Sensor Vascularization

    Directory of Open Access Journals (Sweden)

    Jarel K. Gandhi

    2015-09-01

    Full Text Available Enhanced vascularization at sensor interfaces can improve long-term function. Fibrin, a natural polymer, has shown promise as a biomaterial for sensor coating due to its ability to sustain endothelial cell growth and promote local vascularization. However, the culture of cells, particularly endothelial cells (EC, within 3D scaffolds for more than a few days is challenging due to rapid loss of EC viability. In this manuscript, a robust method for developing fibrin microbead scaffolds for long-term culture of encapsulated ECs is described. Fibrin microbeads are formed using sodium alginate as a structural template. The size, swelling and structural properties of the microbeads were varied with needle gauge and composition and concentration of the pre-gel solution. Endothelial colony-forming cells (ECFCs were suspended in the fibrin beads and cultured within a perfusion bioreactor system. The perfusion bioreactor enhanced ECFCs viability and genome stability in fibrin beads relative to static culture. Perfusion bioreactors enable 3D culture of ECs within fibrin beads for potential application as a sensor coating.

  6. Inhibitive effects of anti-oxidative vitamins on mannitol-induced apoptosis of vascular endothelial cells.

    Science.gov (United States)

    Pan, Kai-yu; Shen, Mei-ping; Ye, Zhi-hong; Dai, Xiao-na; Shang, Shi-qiang

    2006-10-01

    Study blood vessel injury and gene expression indicating vascular endothelial cell apoptosis induced by mannitol with and without administration of anti-oxidative vitamins. Healthy rabbits were randomly divided into four groups. Mannitol was injected into the vein of the rabbit ear in each animal. Pre-treatment prior to mannitol injection was performed with normal saline (group B), vitamin C (group C) and vitamin E (group D). Blood vessel injury was assessed under electron and light microscopy. In a second experiment, cell culture specimen of human umbilical vein endothelial cells were treated with mannitol. Pre-treatment was done with normal saline (sample B), vitamin C (sample C) and vitamin E (sample D). Total RNA was extracted with the original single step procedure, followed by hybridisation and analysis of gene expression. In the animal experiment, serious blood vessel injury was seen in group A and group B. Group D showed light injury only, and normal tissue without pathological changes was seen in group C. Of all 330 apoptosis-related genes analysed in human cell culture specimen, no significant difference was seen after pre-treatment with normal saline, compared with the gene chip without pre-treatment. On the gene chip pre-treated with vitamin C, 45 apoptosis genes were down-regulated and 34 anti-apoptosis genes were up-regulated. Pre-treatment with vitamin E resulted in the down-regulation of 3 apoptosis genes. Vitamin C can protect vascular endothelial cells from mannitol-induced injury.

  7. Update on vascular endothelial Ca(2+) signalling: A tale of ion channels, pumps and transporters.

    Science.gov (United States)

    Moccia, Francesco; Berra-Romani, Roberto; Tanzi, Franco

    2012-07-26

    A monolayer of endothelial cells (ECs) lines the lumen of blood vessels and forms a multifunctional transducing organ that mediates a plethora of cardiovascular processes. The activation of ECs from as state of quiescence is, therefore, regarded among the early events leading to the onset and progression of potentially lethal diseases, such as hypertension, myocardial infarction, brain stroke, and tumor. Intracellular Ca(2+) signals have long been know to play a central role in the complex network of signaling pathways regulating the endothelial functions. Notably, recent work has outlined how any change in the pattern of expression of endothelial channels, transporters and pumps involved in the modulation of intracellular Ca(2+) levels may dramatically affect whole body homeostasis. Vascular ECs may react to both mechanical and chemical stimuli by generating a variety of intracellular Ca(2+) signals, ranging from brief, localized Ca(2+) pulses to prolonged Ca(2+) oscillations engulfing the whole cytoplasm. The well-defined spatiotemporal profile of the subcellular Ca(2+) signals elicited in ECs by specific extracellular inputs depends on the interaction between Ca(2+) releasing channels, which are located both on the plasma membrane and in a number of intracellular organelles, and Ca(2+) removing systems. The present article aims to summarize both the past and recent literature in the field to provide a clear-cut picture of our current knowledge on the molecular nature and the role played by the components of the Ca(2+) machinery in vascular ECs under both physiological and pathological conditions.

  8. Effect of Ligustrazine Injection on Vascular Endothelial Cell of The Patients with Arteriosclerosis Obliterans

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Objective: To study the effect of ligustrazine injection (LI) on vascular endothelial cell of the patients with arteriosclerosis obliterans (ASO) and explore the new pathway of investigating effective vascular protective agents in Chinese medicinal herbs. Methods: Forty-six patients with ASO in the LI group treated by LI were observed, their circulating endothelial cells (CEC) were detected quantitatively before and after treatment. The results were compared with the CEC of 53 cases of healthy persons (control group) in the same period. Results: In the LI group, the immediate cure rate was 45.7% (21 cases), markedly effective rate 36.9% (17 cases) and the effective rate 17.4% (8 cases). The CEC of patients before treatment was 4.39±1.76/0.9μl, which was significantly higher than that of the healthy persons (1.53±0.42/0.9μl). It could be reduced after treatment, along with the improvement of symptoms and signs, to 2.43±0.87/0.9μl, P<0.01. Conclusion: LI in treating ASO not only displays extraordinary effect, but also has good effect in curing the damage of endothelial cells.

  9. C-peptide protects against hyperglycemic memory and vascular endothelial cell apoptosis.

    Science.gov (United States)

    Bhatt, Mahendra Prasad; Lee, Yeon-Ju; Jung, Se-Hui; Kim, Yong Ho; Hwang, Jong Yun; Han, Eun-Taek; Park, Won Sun; Hong, Seok-Ho; Kim, Young-Myeong; Ha, Kwon-Soo

    2016-10-01

    C-peptide exerts protective effects against diabetic complications; however, its role in inhibiting hyperglycemic memory (HGM) has not been elucidated. We investigated the beneficial effect of C-peptide on HGM-induced vascular damage in vitro and in vivo using human umbilical vein endothelial cells and diabetic mice. HGM induced apoptosis by persistent generation of intracellular ROS and sustained formation of ONOO(-) and nitrotyrosine. These HGM-induced intracellular events were normalized by treatment with C-peptide, but not insulin, in endothelial cells. C-peptide also inhibited persistent upregulation of p53 and activation of mitochondrial adaptor p66(shc) after glucose normalization. Further, C-peptide replacement therapy prevented persistent generation of ROS and ONOO(-) in the aorta of diabetic mice whose glucose levels were normalized by the administration of insulin. C-peptide, but not insulin, also prevented HGM-induced endothelial apoptosis in the murine diabetic aorta. This study highlights a promising role for C-peptide in preventing HGM-induced intracellular events and diabetic vascular damage.

  10. Cytokine-Induced Cell Surface Expression of Adhesion Molecules in Vascular Endothelial Cells In vitro

    Institute of Scientific and Technical Information of China (English)

    陈红辉; 刘昌勤; 孙圣刚; 梅元武; 童萼塘

    2001-01-01

    Regulation of the adhesion molecules expression by cytokine in vascular endothelial cells was investigated. Human umbilical vein endothelial cells (HUVEC) were stimulated with cytokines, TNF-α (1-250 U/ml) or IL-1β (0.1-50 U/ml) for 24 h. HUVEC were also cultured with cytokines, TNF-α (100 U/ml) or IL-1β (10 U/ml), for 4-72 h, cell surface expression of adhesion molecules (ICAM-1 and VCAM-1) were detected and quantitated by immunocytochemical methods and computerized imaging analysis technique. Adhesion molecules expression were up-regulated by TNF-α, IL-1β in a concentration- and time-dependent manner. Some significant differences were observed between the effects of cytokines on the ICAM-1 and on VCAM-1 expression. Cytokines might directly induce the expression of ICAM-1 and VCAM-1 in vascular endothelial cells. Our observations indicate differential functions of the two adhesion molecules during the evolution of inflammatory responses in stroke.

  11. Cerebral vascular effects of loading dose of dexmedetomidine: A Transcranial Color Doppler study

    Directory of Open Access Journals (Sweden)

    Appavoo Arulvelan

    2016-01-01

    Full Text Available Background: Dexmedetomidine has been widely used in critical care settings because of its property of maintaining stable hemodynamics and inducing conscious sedation. The use of dexmedetomidine is in increasing trend particularly in patients with neurological disorders. Very few studies have focused on the cerebral hemodynamic effects of dexmedetomidine. This study is aimed to address this issue. Methods: Thirty patients without any intracranial pathology were included in this study. Middle cerebral artery flow velocity obtained from transcranial color Doppler was used to assess the cerebral hemodynamic indices. Mean flow velocity (mFV, pulsatility index (PI, cerebral vascular resistant index (CVRi, estimated cerebral perfusion pressure (eCPP, and zero flow pressure (ZFP were calculated bilaterally at baseline and after infusion of injection Dexmedetomidine 1 mcg/Kg over 10 min. Results: Twenty-six patients completed the study protocol. After administration of loading dose of dexmedetomidine, mFV and eCPP values were significantly decreased in both hemispheres (P < 0.05; PI, CVRi, and ZFP values showed significant increase (P < 0.05 after dexmedetomidine infusion. Conclusion: Increase in PI, CVRi, and ZFP suggests that there is a possibility of an increase in distal cerebral vascular resistance (CVR with loading dose of dexmedetomidine. Decrease in mFV and eCPP along with an increase in CVR may lead to a decrease in cerebral perfusion. This effect can be exaggerated in patients with preexisting neurological illness. Further studies are needed to evaluate the effect of dexmedetomidine on various other pathological conditions involving brain like traumatic brain injury and vascular malformations.

  12. Endovascular treatment of cerebral aneurysms at Altai Regional Vascular Center

    Directory of Open Access Journals (Sweden)

    Д. А. Долженко

    2015-10-01

    Full Text Available A retrospective analysis of the results of endovascular treatment of patients with the brain aneurysms was carried out at the Neurosurgical Department of Regional Clinical Hospital in Barnaul over a period from 2009 to 2011. 52 patients with 57 cerebral aneurysms were included in the study and 55 endovascular interventions were performed. Total embolization (type A was used in 77% of patients, embolization type B was performed in 19% of cases, incomplete embolization (type C occurred in 4% of cases. 14 (26,9% patients were operated in the acute period of SAH. Conclusions are made relating to the effectiveness and relative safety of intravascular treatment of aneurysms, the need for differentiated approaches to the tactics of surgical treatment of patients in the acute period of hemorrhagic stroke due to the rupture of a cerebral aneurysm.

  13. Loss of NF1 expression in human endothelial cells promotes autonomous proliferation and altered vascular morphogenesis.

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    Anshika Bajaj

    Full Text Available Neurofibromatosis is a well known familial tumor syndrome, however these patients also suffer from a number of vascular anomalies. The loss of NFl from the endothelium is embryonically lethal in mouse developmental models, however little is known regarding the molecular regulation by NF1 in endothelium. We investigated the consequences of losing NF1 expression on the function of endothelial cells using shRNA. The loss of NF1 was sufficient to elevate levels of active Ras under non-stimulated conditions. These elevations in Ras activity were associated with activation of downstream signaling including activation of ERK, AKT and mTOR. Cells knocked down in NF1 expression exhibited no cellular senescence. Rather, they demonstrated augmented proliferation and autonomous entry into the cell cycle. These proliferative changes were accompanied by enhanced expression of cyclin D, phosphorylation of p27(KIP, and decreases in total p27(KIP levels, even under growth factor free conditions. In addition, NF1-deficient cells failed to undergo normal branching morphogenesis in a co-culture assay, instead forming planar islands with few tubules and branches. We find the changes induced by the loss of NF1 could be mitigated by co-expression of the GAP-related domain of NF1 implicating Ras regulation in these effects. Using doxycycline-inducible shRNA, targeting NF1, we find that the morphogenic changes are reversible. Similarly, in fully differentiated and stable vascular-like structures, the silencing of NF1 results in the appearance of abnormal vascular structures. Finally, the proliferative changes and the abnormal vascular morphogenesis are normalized by low-dose rapamycin treatment. These data provide a detailed analysis of the molecular and functional consequences of NF1 loss in human endothelial cells. These insights may provide new approaches to therapeutically addressing vascular abnormalities in these patients while underscoring a critical role for

  14. Disturbance of copper homeostasis is a mechanism for homocysteine-induced vascular endothelial cell injury.

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    Daoyin Dong

    Full Text Available Elevation of serum homocysteine (Hcy levels is a risk factor for cardiovascular diseases. Previous studies suggested that Hcy interferes with copper (Cu metabolism in vascular endothelial cells. The present study was undertaken to test the hypothesis that Hcy-induced disturbance of Cu homeostasis leads to endothelial cell injury. Exposure of human umbilical vein endothelial cells (HUVECs to concentrations of Hcy at 0.01, 0.1 or 1 mM resulted in a concentration-dependent decrease in cell viability and an increase in necrotic cell death. Pretreatment of the cells with a final concentration of 5 µM Cu in cultures prevented the effects of Hcy. Hcy decreased intracellular Cu concentrations. HPLC-ICP-MS analysis revealed that Hcy caused alterations in the distribution of intracellular Cu; more Cu was redistributed to low molecular weight fractions. ESI-Q-TOF detected the formation of Cu-Hcy complexes. Hcy also decreased the protein levels of Cu chaperone COX17, which was accompanied by a decrease in the activity of cytochrome c oxidase (CCO and a collapse of mitochondrial membrane potential. These effects of Hcy were all preventable by Cu pretreatment. The study thus demonstrated that Hcy disturbs Cu homeostasis and limits the availability of Cu to critical molecules such as COX17 and CCO, leading to mitochondrial dysfunction and endothelial cell injury.

  15. [Medical significance of endothelial glycocalyx. Part 2: Its role in vascular diseases and in diabetic complications].

    Science.gov (United States)

    Frati Munari, Alberto C

    2014-01-01

    Endothelial glycocalyx is a layer composed by glycosaminoglycans, proteoglycans and glycoproteins attached to the vascular endothelial luminal surface. Shredding of glycocalyx appears as an essential initial step in the pathophysiology of atherosclerosis and microangiopathic complications of diabetes mellitus, as well as in chronic venous disease. Atherosclerosis risk factors, as hypercholesterolemia (LDL), hyperglycemia, inflammation, salt excess and altered shear stress can damage glycocalyx. This lead to endothelial dysfunction and allows LDL and leukocytes to filtrate to the subendothelial space initiating atheroma plaque formation. Degradation of glycocalyx in diabetes mellitus is mainly due to oxidative stress and enables protein filtration (albuminuria) and endothelial disorder of microangiopathy. Chronic venous hypertension brings to altered shears stress which results in shredded glycocalyx, this allows leukocytes to migrate into venous wall and initiate inflammation leading to morphologic and functional venous changes of the chronic venous disease. Treatment with glycosaminoglycans (sulodexide) prevents or recovers the damaged glycocalyx and several of its consequences. This drug improves chronic venous disease and promotes healing of chronic venous ulcers. It has also been useful in peripheral arterial obstructive disease and in diabetic nephropathy with albuminuria.

  16. The Mechanical Study of Vascular Endothelial Growth Factor on the Prevention of Restenosis after Angioplasty

    Institute of Scientific and Technical Information of China (English)

    LIU Qigong; LU Zaiying; ZHOU Honglian; YAN Jin; ZHANG Weidong

    2001-01-01

    The mechanism of vascular endothelial growth factor (VEGF) on the prevention of restenosis after angioplasty was investigated. The cultured vascular endothelial cells (VEC) were incubated with the conditioned medium (CM) from vascular smooth muscle cells (VSMC) infected with recombinant adenoviruses containing the hVEGF165 gene. To observe the effects of VEGF on proliferation and NO, ET, 6-keto-PGF1α secretion of VEC, WST-1 method, Griess method and radioimmunoassay were used respectively. The PDGF-B mRNA transcription in VECs was detected by RT-PCR. It was showed that NO, 6-keto-PGF1α and OD value were markedly increased in a dosedependent manner in the VEGF-treated groups as compared with those in the control group, while ET and PDGF-B mRNA were significantly decreased in the VEGF-treated groups (P<0. 05 or P<0. 01). Adenovirus vector mediated hVEGF165 gene could promote the proliferation of VECs and im prove NO, PGI2 secretion, inhibit ET secretionand PDGF-B mRNA transcription in the VECs. Theabove results offered further theoretical evidence for VEGF on the prevention of restenosis after angioplasty.

  17. Understanding the effects of mature adipocytes and endothelial cells on fatty acid metabolism and vascular tone in physiological fatty tissue for vascularized adipose tissue engineering.

    Science.gov (United States)

    Huber, Birgit; Volz, Ann-Cathrin; Kluger, Petra J

    2015-11-01

    Engineering of large vascularized adipose tissue constructs is still a challenge for the treatment of extensive high-graded burns or the replacement of tissue after tumor removal. Communication between mature adipocytes and endothelial cells is important for homeostasis and the maintenance of adipose tissue mass but, to date, is mainly neglected in tissue engineering strategies. Thus, new co-culture strategies are needed to integrate adipocytes and endothelial cells successfully into a functional construct. This review focuses on the cross-talk of mature adipocytes and endothelial cells and considers their influence on fatty acid metabolism and vascular tone. In addition, the properties and challenges with regard to these two cell types for vascularized tissue engineering are highlighted.

  18. Study of Microvessel Density and the Expression of Vascular Endothelial Growth Factors in Adrenal Gland Pheochromocytomas

    Directory of Open Access Journals (Sweden)

    Magdalena Białas

    2014-01-01

    Full Text Available Angiogenesis (neoangiogenesis, a process of neovascularization, is an essential step for local tumor growth and distant metastasis formation. We have analysed angiogenesis status: vascular architecture, microvessel density, and vascular endothelial growth factors expression in 62 adrenal pheochromocytomas: 57 benign and 5 malignant. Immunohistochemical evaluation revealed that vascular architecture and vessel density are different in the central and subcapsular areas of the tumor. Furthermore, we have observed a strong correlation between number of macrophages and microvessel density in the central and subcapsular areas of the tumor and between the expression of VEGF-A in tumor cells and microvessel density in central and subcapsular areas of the tumor. Secondary changes in these tumors influence the results and both vascular architecture and microvessel density are markedly disturbed by hemorrhagic and cystic changes in pheochromocytomas. These changes are partially caused by laparoscopic operation technique. However, no differences in vascular parameters were found between pheochromocytomas with benign and malignant clinical behavior. Our observation showed that analysis of angiogenesis, as a single feature, does not help in differentiating malignant and benign pheochromocytomas and has no independent prognostic significance. On the other hand, high microvessel density in pheochromocytoma is a promising factor for antiangiogenic therapy in malignant cases.

  19. Human vascular smooth muscle cells and endothelial cells cocultured on polyglycolic acid (70/30) scaffold in tissue engineered vascular graft

    Institute of Scientific and Technical Information of China (English)

    WEN Shao-jun; ZHAO Li-min; WANG Shen-guo; LI Jing-xing; CHEN Hua-ying; LIU Jie-lin; LIU Ya; LUO Yi; Roo Changizi

    2007-01-01

    Background Current prosthetic, small diameter vascular grafts showing poor long term patency rates have led to the pursuit of other biological materials. Biomaterials that successfully integrate into surrounding tissue should match not only the mechanical properties of tissues, but also topography. Polyglycolic acid (70/30) has been used as synthetic grafts to determine whether human vascular smooth muscle cells and endothelial cells attach, survive and secrete endothelin and 6-keto-prostaglandin F1α (6-keto-PGF1α).Methods Endothelial cells and smooth muscle cells were isolated from adult human great saphenous vein. They were seeded on polyglycolic acid scaffold in vitro separately to grow vascular patch (Groups A and B respectively) and cocultured in vitro to grow into vascular patch (Group C). Smooth muscle cells and endothelial cells were identified by immunohistochemical analysis and growth of cells on polyglycolic acid was investigated using scanning electron microscopy. The levels of endothelin and 6-keto-PGF1α in the culturing solutions were examined by radioimmunology to measure endothelial function.Results Seed smooth muscle cells adhered to polyglycolic acid scaffold and over 28 days grew in the interstices to form a uniform cell distribution throughout the scaffold. Then seed endothelial cells formed a complete endothelial layer on the smooth muscle cells. The levels of endothelin and 6-keto-prostaglandin F1 alpha in the culturing solution were (234±29) pg/ml and (428+98) pg/ml respectively in Group C and (196+30) pg/ml and (346±120) pg/ml in Group B; both significantly higher than in Groups A and D (blank control group, all P<0.05 ).Conclusions Cells could be grown successfully on polyglycolic acid and retain functions of secretion. Our next step is to use human saphenous vein smooth muscle cells and endothelial cells to grow tubular vascular grafts in vitro.

  20. Dual delivery of vascular endothelial growth factor and hepatocyte growth factor coacervate displays strong angiogenic effects.

    Science.gov (United States)

    Awada, Hassan K; Johnson, Noah R; Wang, Yadong

    2014-05-01

    Controlled delivery of multiple growth factors (GFs) holds great potential for the clinical treatment of ischemic diseases and might be more therapeutically effective to reestablish vasculature than the provision of a single GF. Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) are two potent angiogenic factors. However, due to rapid degradation and dilution in the body, their clinical potential will rely on an effective mode of delivery. A coacervate, composed of heparin and a biodegradable polycation, which protects GFs from proteolysis and potentiates their bioactivities, is developed. Here, the coacervate incorporates VEGF and HGF and sustains their release for at least three weeks. Their strong angiogenic effects on endothelial cell proliferation and tube formation in vitro are confirmed. Furthermore, it is demonstrated that coacervate-based delivery of these factors has stronger effects than free application of both factors and to coacervate delivery of each GF separately.

  1. MEK1/2 inhibition attenuates vascular ETA and ETB receptor alterations after cerebral ischaemia

    DEFF Research Database (Denmark)

    Henriksson, Marie; Stenman, Emelie; Vikman, Petter;

    2007-01-01

    Cerebral ischaemia is associated with elevated levels of endothelin B (ETB) receptors in the ipsilateral middle cerebral artery (MCA). This up-regulation of ET receptors occurs via de novo transcription involving mitogen-activated protein kinases (MAPK). The aim of this study was to examine the e......, neurological symptoms, and ET receptor alteration. The vascular effects of U0126 provide new perspective on possible mechanisms of actions of MAPK inhibition in cerebral ischaemia.......Cerebral ischaemia is associated with elevated levels of endothelin B (ETB) receptors in the ipsilateral middle cerebral artery (MCA). This up-regulation of ET receptors occurs via de novo transcription involving mitogen-activated protein kinases (MAPK). The aim of this study was to examine...... the effect of inhibition of the MAP kinase/ERK kinase (MEK)1/2 on ET receptor alteration, brain damage, and neurology in experimental cerebral ischaemia. Transient middle cerebral artery occlusion (MCAO) was induced in male Wistar rats by the intraluminal filament technique. The animals received 100 mg...

  2. Cerebral vascular findings in PAPA syndrome: cerebral arterial vasculopathy or vasculitis and a posterior cerebral artery dissecting aneurysm.

    Science.gov (United States)

    Khatibi, Kasra; Heit, Jeremy J; Telischak, Nicholas A; Elbers, Jorina M; Do, Huy M

    2016-08-01

    A young patient with PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne) syndrome developed an unusual cerebral arterial vasculopathy/vasculitis (CAV) that resulted in subarachnoid hemorrhage from a ruptured dissecting posterior cerebral artery (PCA) aneurysm. This aneurysm was successfully treated by endovascular coil sacrifice of the affected segment of the PCA. The patient made an excellent recovery with no significant residual neurologic deficit.

  3. A PROSPECTIVE, OBSERVATIONAL STUDY OF SOLUBLE FLT-1 AND VASCULAR ENDOTHELIAL GROWTH FACTOR IN SEPSIS

    Science.gov (United States)

    Shapiro, Nathan I.; Yano, Kiichiro; Okada, Hitomi; Fischer, Christopher; Howell, Michael; Spokes, Katherine C.; Ngo, Long; Angus, Derek C.; Aird, William C.

    2012-01-01

    Prior murine and human studies suggest that vascular endothelial growth factor (VEGF) contributes to endothelial cell activation and severity of illness in sepsis. Furthermore, circulating levels of soluble VEGF receptor 1 (sFLT) levels were found to increase as part of the early response to sepsis in mice. The objective of the study was to evaluate the blood levels of free VEGF-A and sFLT in patients presenting to the emergency department (ED) with suspected infection and to assess the relationship of these levels with severity of illness and inflammation. It was a prospective, observational study initiated in the ED of an urban, tertiary care, university hospital. Inclusion criteria were (1) ED patients aged 18 years or older and (2) clinical suspicion of infection. Eighty-three patients were enrolled in the study. The major findings were that (1) the mean VEGF and sFLT levels were increasingly higher across the following groups: noninfected control patients, infected patients without shock, and septic shock patients; (2) initial and 24-h VEGF levels had a significant correlation with the presence of septic shock at 24 h; (3) initial and 24-h sFLT levels correlated with Acute Physiology Age Chronic Health Evaluation II and Sepsis-related Organ Failure Assessment scores initially and at 24 h; and (4) VEGF and sFLT levels correlated with inflammatory cascade activation. This is the first report of sFLT as a potential new marker of severity in patients with sepsis. Vascular endothelial cell growth factor and its signaling axis are important in the endothelial cell response to sepsis, and further elucidation of these mechanisms may lead to advances in future diagnostic and therapeutic opportunities. PMID:18598002

  4. Impaired vascular endothelial function in patients with restless legs syndrome: a new aspect of the vascular pathophysiology.

    Science.gov (United States)

    Koh, Seung Yon; Kim, Min Seung; Lee, Sun Min; Hong, Ji Man; Yoon, Jung Han

    2015-12-15

    Restless legs syndrome (RLS) is a common sleep disorder in which patients feel unpleasant leg sensations and the urge to move their legs during rest, particularly at night. Leg movement improves these symptoms. Although several studies have demonstrated an association between cardiovascular disease and RLS, the mechanisms underlying this relationship remain unclear. Recent studies have shown changes in the peripheral microvasculature, including altered blood flow and capillary tortuosity, and peripheral hypoxia. Vascular endothelial dysfunction can be assessed noninvasively with ultrasound measurements of brachial artery flow-mediated dilatation (FMD). Therefore, this study investigated FMD in RLS patients to determine the involvement of microvascular alterations in this disorder. The study enrolled 25 drug-naïve RLS patients and 25 sex- and age-matched controls and compared the FMD values of the two groups. RLS was diagnosed according to the criteria of the International Restless Legs Syndrome Study Group. FMD was significantly lower in the RLS patients (6.6 ± 1.2%) compared to the controls (8.4 ± 1.8%; p<0.05) and the RLS patients showed a weak, negative correlation between RLS severity and FMD (r=-0.419, p=0.04). Multivariate linear regression analysis revealed that RLS (B=-1.87, 95% confidence interval [CI] -2.72 to -1.02; p<0.001) and age (B=-0.06; 95% CI -0.12 to -0.02; p<0.001) were significantly and inversely correlated with FMD. This study demonstrated that RLS patients have poorer vascular endothelial function than normal healthy subjects and provides further evidence supporting the involvement of peripheral systems in the generation of RLS. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Prostaglandin E2 and vascular endothelial growth factor A mediate angiogenesis of human ovarian follicular endothelial cells

    Science.gov (United States)

    Trau, Heidi A.; Brännström, Mats; Curry, Thomas E.; Duffy, Diane M.

    2016-01-01

    STUDY QUESTION Which receptors for prostaglandin E2 (PGE2) and vascular endothelial growth factor A (VEGFA) mediate angiogenesis in the human follicle around the time of ovulation? SUMMARY ANSWER PGE2 and VEGFA act via multiple PGE2 receptors (PTGERs) and VEGF receptors (VEGFRs) to play complementary roles in follicular angiogenesis. WHAT IS KNOWN ALREADY Production of PGE2 and VEGFA by the follicle are prerequisites for ovulation. PGE2 is an emerging regulator of angiogenesis and has not been examined in the context of the human ovulatory follicle. VEGFA is an established regulator of follicular angiogenesis. STUDY DESIGN, SIZE, DURATION Ovarian biopsies containing the ovulatory follicle were obtained from 11 women of reproductive age (30–45 years) undergoing surgery for laparoscopic sterilization. In some cases, women received hCG to substitute for the ovulatory LH surge before ovarian biopsy. In addition, aspirates from four women of reproductive age (18–31 years) undergoing gonadotrophin stimulation for oocyte donation were obtained for isolation of human ovarian microvascular endothelial cells (hOMECs). PARTICIPANTS/MATERIALS, SETTING, METHODS Ovarian biopsies were utilized for immunocytochemical detection of von Willebrand factor to identify endothelial cells. hOMECs were cultured with PGE2, PTGER receptor selective agonists, VEGFA, or VEGFR selective agonists. hOMECs were assessed for proliferation by Ki67 immunocytochemistry. hOMEC migration was determined by counting cells which migrated through a porous membrane in vitro. Sprout formation was quantified by determining sprout number and length from photographs take after culture of hOMECs in a 3-dimensional matrix. MAIN RESULTS AND THE ROLE OF CHANCE Endothelial cells were not observed within the granulosa cell layer of human ovulatory follicles prior to an ovulatory dose of hCG and were first seen amongst granulosa cells 18–34 h after hCG. In vitro, PGE2 enhanced migration and sprout formation but

  6. Effects of Azardirachta indica on Vascular Endothelial Growth Factor and Cytokines in Diabetic Deep Wound.

    Science.gov (United States)

    Gautam, Manish Kumar; Gangwar, Mayank; Singh, Surya Kumar; Goel, Raj Kumar

    2015-06-01

    A chronic, unhealed diabetic wound is one of the severe complications of diabetes mellitus. Azadirachta indica has been reported to have antidiabetic and antiapoptotic properties. The present work incorporates the healing potential of 50 % ethanol A. indica leaves extract against deep surgical wounds in streptozotocin-induced mild diabetic rats. A. indica leaves extract (500 mg/kg) was administered orally, once daily for ten days. Serum glucose, cholesterol, and triglycerides as well as body weight, food, and water intake, and tissue antioxidants (catalase, superoxide dismutase and reduced glutathione), free radicals (lipid peroxidation and nitric oxide), myeloperoxidase, total collagens (hydroxyproline, hexuronic acid and hexosamine), protein, vascular endothelial growth factor, and cytokines (tumor necrotic factor-α and interleukin-1β) were estimated. Histology was done for connective tissue formation and inflammatory and healing in deep granulation tissue after A. indica leaves extract treatment. Diabetic rats showed an increase in serum glucose, cholesterol, and triglycerides levels, food and water intake, and granular tissue free radicals, myeloperoxidase, and cytokines, but a decrease in body weight, total collagen, and vascular endothelial growth factor levels. A. indica leaves extract reversed the increased serum glucose, cholesterol, and triglycerides, food and water intake, and tissue free radicals, myeloperoxidase and, cytokines, but increased body weight, tissue antioxidants, total collagen, and vascular endothelial growth factor contents. The results thus indicated an improvement in wound healing by A. indica leaves extract in diabetic rats through enhanced angiogenesis mediated through the inhibition of hyperglycemia, oxidative stress, and down- and upregulation of inflammatory mediators and growth factor expression.

  7. Activation of adenosine A2A receptors by polydeoxyribonucleotide increases vascular endothelial growth factor and protects against testicular damage induced by experimental varicocele in rats.

    Science.gov (United States)

    Minutoli, Letteria; Arena, Salvatore; Bonvissuto, Giulio; Bitto, Alessandra; Polito, Francesca; Irrera, Natasha; Arena, Francesco; Fragalà, Eugenia; Romeo, Carmelo; Nicotina, Piero Antonio; Fazzari, Carmine; Marini, Herbert; Implatini, Alessandra; Grimaldi, Silvia; Cantone, Noemi; Di Benedetto, Vincenzo; Squadrito, Francesco; Altavilla, Domenica; Morgia, Giuseppe

    2011-03-15

    In rat experimental varicocele, polydeoxyribonucleotide (PDRN) induces vascular endothelial growth factor (VEGF) production, thereby enhancing testicular function. This may point to a new therapeutic approach in human varicocele.

  8. Inducing effects of hepatocyte growth factor on the expression of vascular endothelial growth factor in human colorectal carcinoma cells through MEK and PI3K signaling pathways

    Institute of Scientific and Technical Information of China (English)

    ZHANG Yu-hua; WEI Wei; XU Hao; WANG Yan-yan; WU Wen-xi

    2007-01-01

    Background Vascular endothelial growth factor plays a key role in human colorectal carcinoma invasion and metastasis. However, the regulation mechanism remains unknown. Recent studies have shown that several cytokines can regulate the expression of vascular endothelial growth factor in tumor cells. In this study, we investigated whether hepatocyte growth factor can regulate the expression of vascular endothelial growth factor in colorectal carcinoma cells.Methods Hepatocyte growth factor and vascular endothelial growth factor in human serum were measured by ELISA.The mRNA level of vascular endothelial growth factor was analyzed by reverse transcription-PCR. Western blot assay was performed to evaluate levels of c-Met and several other proteins involved in the MAPK and PI3K signaling pathways in colorectal carcinoma cells.Results Serum hepatocyte growth factor and vascular endothelial growth factor were significantly increased in colorectal carcinoma subjects. In vitro extraneous hepatocyte growth factor markedly increased protein and mRNA levels of vascular endothelial growth factor in colorectal carcinoma cells. Hepatocyte growth factor induced phosphorylation of c-Met, ERK1/2 and AKT in a dose-dependent manner. Specific inhibitors on MEK and PI3K inhibited the hepatocyte growth factor-induced expression of vascular endothelial growth factor in colorectal carcinoma cells.Conclusion This present study indicates that hepatocyte growth factor upregulates the expression of vascular endothelial growth factor in colorectal carcinoma cells via the MEK/ERK and PI3K/AKT signaling pathways.

  9. Vascular risk factors, atherosclerosis, cerebral white matter lesions and cerebral perfusion in a population-based study

    Energy Technology Data Exchange (ETDEWEB)

    Claus, J.J. [Dept. of Epidemiology and Biostatistics, Erasmus Univ. Medical School, Rotterdam (Netherlands); Breteler, M.M.B. [Dept. of Epidemiology and Biostatistics, Erasmus Univ. Medical School, Rotterdam (Netherlands); Hasan, D. [Dept. of Neurology, Univ. Hospital Rotterdam Dijkzigt, Rotterdam (Netherlands); Krenning, E.P. [Dept. of Nuclear Medicine, Univ. Hospital Rotterdam Dijkzigt, Rotterdam (Netherlands); Bots, M.L. [Dept. of Epidemiology and Biostatistics, Erasmus Univ. Medical School, Rotterdam (Netherlands); Grobbee, D.E. [Dept. of Epidemiology and Biostatistics, Erasmus Univ. Medical School, Rotterdam (Netherlands); Swieten, J.C. van [Dept. of Neurology, Univ. Hospital Rotterdam Dijkzigt, Rotterdam (Netherlands); Harskamp, F. van [Dept. of Neurology, Univ. Hospital Rotterdam Dijkzigt, Rotterdam (Netherlands); Hofman, A. [Dept. of Epidemiology and Biostatistics, Erasmus Univ. Medical School, Rotterdam (Netherlands)

    1996-06-01

    We studied risk factors for cerebral vascular disease (blood pressure and hypertension, factor VIIc, factor VIIIc, fibrinogen), indicators of atherosclerosis (intima-media thickness and plaques in the carotid artery) and cerebral white matter lesions in relation to regional cerebral blood flow (rCBF) in 60 persons (aged 65-85 years) recruited from a population-based study. rCBF was assessed with single-photon emission tomography using technetium-99m d,l-hexamethylpropylene amine oxime ({sup 99m}Tc-HMPAO). Statistical analysis was performed with multiple linear regression with adjustment for age, sex and ventricle-to-brain ratio. A significant positive association was found between systolic and diastolic blood pressure and temporo-parietal rCBF. In analysis with quartiles of the distribution, we found a threshold effect for the relation of low diastolic blood pressure ({<=}60 mmHg) and low temporo-parietal rCBF. Levels of plasma fibrinogen were inversely related to parietal rCBF, with a threshold effect of high fibrinogen levels (>3.2 g/l) and low rCBF. Increased atherosclerosis was related to low rCBF in all cortical regions, but these associations were not significant. No consistent relation was observed between severity of cerebral white matter lesions and rCBF. Our results may have implications for blood pressure control in the elderly population. (orig.)

  10. Intraocular and systemic levels of vascular endothelial growth factor in advanced cases of retinopathy of prematurity

    Directory of Open Access Journals (Sweden)

    Raul Velez-Montoya

    2010-08-01

    Full Text Available Raul Velez-Montoya1, Carmen Clapp2, Jose Carlos Rivera2, Gerardo Garcia-Aguirre1, Virgilio Morales-Cantón1, Jans Fromow-Guerra1, Jose Luis Guerrero-Naranjo1, Hugo Quiroz-Mercado31Retina Department Asociación para Evitar la Ceguera en México IAP, México City, México; 2Department of Cellular and Molecular Neurobiology, Universidad Nacional Autónoma de México, Querétaro, México; 3Department of Ophthalmology, Denver Health Medical Center, University of Colorado School of Medicine, Colorado, USAPurpose: To measure vitreous, aqueous, subretinal fluid and plasma levels of vascular ­endothelial growth factor in late stages of retinopathy of prematurity.Methods: Interventional study. We enrolled patients with clinical diagnoses of bilateral stage V retinopathy of prematurity, confirmed by b-scan ultrasound and programmed for vitrectomy. During surgery we took samples from blood, aqueous, vitreous, and subretinal fluids. The vascular endothelial growth factor concentration in each sample was measured by ELISA reaction. A control sample of aqueous, vitreous and blood was taken from patients with congenital cataract programmed for phacoemulsification. For statistical analysis, a Mann–Whitney and a Wilcoxon W test was done with a significant P value of 0.05.Results: We took samples of 16 consecutive patients who met the inclusion criteria. The vascular endothelial growth factor levels in the study group were: aqueous, 76.81 ± 61.89 pg/mL; vitreous, 118.53 ± 65.87 pg/mL; subretinal fluid, 1636.58 ± 356.47 pg/mL; and plasma, 74.64 ± 43.94 pg/mL. There was a statistical difference between the study and the control group (P < 0.001 in the aqueous and vitreous samples.Conclusion: Stage 5 retinopathy of prematurity has elevated intraocular levels of vascular endothelial growth factor, which remains high despite severe retinal lesion. There was no ­statistical difference in plasma levels of the molecule between the control and study group

  11. Placenta growth factor and vascular endothelial growth factor B expression in the hypoxic lung

    LENUS (Irish Health Repository)

    Sands, Michelle

    2011-01-25

    Abstract Background Chronic alveolar hypoxia, due to residence at high altitude or chronic obstructive lung diseases, leads to pulmonary hypertension, which may be further complicated by right heart failure, increasing morbidity and mortality. In the non-diseased lung, angiogenesis occurs in chronic hypoxia and may act in a protective, adaptive manner. To date, little is known about the behaviour of individual vascular endothelial growth factor (VEGF) family ligands in hypoxia-induced pulmonary angiogenesis. The aim of this study was to examine the expression of placenta growth factor (PlGF) and VEGFB during the development of hypoxic pulmonary angiogenesis and their functional effects on the pulmonary endothelium. Methods Male Sprague Dawley rats were exposed to conditions of normoxia (21% O2) or hypoxia (10% O2) for 1-21 days. Stereological analysis of vascular structure, real-time PCR analysis of vascular endothelial growth factor A (VEGFA), VEGFB, placenta growth factor (PlGF), VEGF receptor 1 (VEGFR1) and VEGFR2, immunohistochemistry and western blots were completed. The effects of VEGF ligands on human pulmonary microvascular endothelial cells were determined using a wound-healing assay. Results Typical vascular remodelling and angiogenesis were observed in the hypoxic lung. PlGF and VEGFB mRNA expression were significantly increased in the hypoxic lung. Immunohistochemical analysis showed reduced expression of VEGFB protein in hypoxia although PlGF protein was unchanged. The expression of VEGFA mRNA and protein was unchanged. In vitro PlGF at high concentration mimicked the wound-healing actions of VEGFA on pulmonary microvascular endothelial monolayers. Low concentrations of PlGF potentiated the wound-healing actions of VEGFA while higher concentrations of PlGF were without this effect. VEGFB inhibited the wound-healing actions of VEGFA while VEGFB and PlGF together were mutually antagonistic. Conclusions VEGFB and PlGF can either inhibit or potentiate the

  12. Effect of essential fatty acids on glucose-induced cytotoxicity to retinal vascular endothelial cells

    Directory of Open Access Journals (Sweden)

    Shen Junhui

    2012-07-01

    Full Text Available Abstract Background Diabetic retinopathy is a major complication of dysregulated hyperglycemia. Retinal vascular endothelial cell dysfunction is an early event in the pathogenesis of diabetic retinopathy. Studies showed that hyperglycemia-induced excess proliferation of retinal vascular endothelial cells can be abrogated by docosahexaenoic acid (DHA, 22:6 ω-3 and eicosapentaenoic acid (EPA, 20:5 ω-3. The influence of dietary omega-3 PUFA on brain zinc metabolism has been previously implied. Zn2+ is essential for the activity of Δ6 desaturase as a co-factor that, in turn, converts essential fatty acids to their respective long chain metabolites. Whether essential fatty acids (EFAs α-linolenic acid and linoleic acid have similar beneficial effect remains poorly understood. Methods RF/6A cells were treated with different concentrations of high glucose, α-linolenic acid and linoleic acid and Zn2+. The alterations in mitochondrial succinate dehydrogenase enzyme activity, cell membrane fluidity, reactive oxygen species generation, SOD enzyme and vascular endothelial growth factor (VEGF secretion were evaluated. Results Studies showed that hyperglycemia-induced excess proliferation of retinal vascular endothelial cells can be abrogated by both linoleic acid (LA and α-linolenic acid (ALA, while the saturated fatty acid, palmitic acid was ineffective. A dose–response study with ALA showed that the activity of the mitochondrial succinate dehydrogenase enzyme was suppressed at all concentrations of glucose tested to a significant degree. High glucose enhanced fluorescence polarization and microviscocity reverted to normal by treatment with Zn2+ and ALA. ALA was more potent that Zn2+. Increased level of high glucose caused slightly increased ROS generation that correlated with corresponding decrease in SOD activity. ALA suppressed ROS generation to a significant degree in a dose dependent fashion and raised SOD activity significantly. ALA suppressed

  13. Weight loss induced by tyrosine kinase inhibitors of the vascular endothelial growth factor pathway.

    Science.gov (United States)

    Desar, Ingrid M E; Thijs, Annemarie M J; Mulder, Sasja F; Tack, Cees J J; van Herpen, Carla M L; van der Graaf, Winette T A

    2012-02-01

    Weight loss, cachexia and sarcopenia are profound problems in the frail oncologic patients. With the development and increasing use of angiogenesis inhibitors in metastatic cancer patients, the question arises as to their influence on body weight and composition. Angiogenesis is not only important for the growth, development and metastatic potential of tumors but also for physiological processes in adipogenesis. A less known approach of angiogenesis inhibitors is their experimental use in obese models. This review focuses on the effects on the body weight and composition of angiogenesis inhibitors, especially of those targeting the vascular endothelial growth factor pathway.

  14. Placenta growth factor and vascular endothelial growth factor B expression in the hypoxic lung

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    McLoughlin Paul

    2011-01-01

    Full Text Available Abstract Background Chronic alveolar hypoxia, due to residence at high altitude or chronic obstructive lung diseases, leads to pulmonary hypertension, which may be further complicated by right heart failure, increasing morbidity and mortality. In the non-diseased lung, angiogenesis occurs in chronic hypoxia and may act in a protective, adaptive manner. To date, little is known about the behaviour of individual vascular endothelial growth factor (VEGF family ligands in hypoxia-induced pulmonary angiogenesis. The aim of this study was to examine the expression of placenta growth factor (PlGF and VEGFB during the development of hypoxic pulmonary angiogenesis and their functional effects on the pulmonary endothelium. Methods Male Sprague Dawley rats were exposed to conditions of normoxia (21% O2 or hypoxia (10% O2 for 1-21 days. Stereological analysis of vascular structure, real-time PCR analysis of vascular endothelial growth factor A (VEGFA, VEGFB, placenta growth factor (PlGF, VEGF receptor 1 (VEGFR1 and VEGFR2, immunohistochemistry and western blots were completed. The effects of VEGF ligands on human pulmonary microvascular endothelial cells were determined using a wound-healing assay. Results Typical vascular remodelling and angiogenesis were observed in the hypoxic lung. PlGF and VEGFB mRNA expression were significantly increased in the hypoxic lung. Immunohistochemical analysis showed reduced expression of VEGFB protein in hypoxia although PlGF protein was unchanged. The expression of VEGFA mRNA and protein was unchanged. In vitro PlGF at high concentration mimicked the wound-healing actions of VEGFA on pulmonary microvascular endothelial monolayers. Low concentrations of PlGF potentiated the wound-healing actions of VEGFA while higher concentrations of PlGF were without this effect. VEGFB inhibited the wound-healing actions of VEGFA while VEGFB and PlGF together were mutually antagonistic. Conclusions VEGFB and PlGF can either inhibit or

  15. Role of vascular endothelial growth factor in reconstructive surgery after surgical excision of malignant tumor

    Institute of Scientific and Technical Information of China (English)

    麻鹏; 刘春丽

    2008-01-01

    As a key mediator of normal physiological angiogenesis,vascular endothelial growth factor(VEGF)has been regarded as an emancipator to plastic surgeon,and yet a misfortune to oncology surgeon,due to its sin-gular biological effect.Therefore in some clinical cases,especially for some malignant tumor patients having en-dured radical surgery and being craving for a reconstructive surgery,VEGF plays a role full of paradoxes.To make a clinical balance,we should find a point to inhibit tumor cell from utilizing VEGF and make a permission to normal tissues to employ it.

  16. Glutamate enhances the expression of vascular endothelial growth factor in cultured SD rat astrocytes

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Objective To study the effect of glutamate on the expression of vascular endothelial growth factor (VEGF) mRNA and protein in cultured rat astrocytes. Methods Cultured rat astrocytes were randomly divided into 6 groups:control group (C),glutamate group (G),QA group (Q),DCG-IV group (D),L-AP4 group (L) and glutamate+MCPG group (G+M). Cells were cultured under nomoxic condition (95% air,5% CO2). RT-PCR and ELISA methods were used to detect the expression of VEGF mRNA and protein in cultured astrocytes,respect...

  17. Surgical choroidal neovascular membrane removal in the era of anti-vascular endothelial growth factor agents

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    Nagpal Manish

    2009-01-01

    Full Text Available Intravitreal anti-vascular endothelial growth factor (VEGF agents have obtained acceptance as the mainstay in the management strategy of subfoveal choroidal neovascular membranes (CNVM due to varying etiologies. Few drawbacks include need for repeated intravitreal injections, with its adjunct risks, and the lack of a predefined treatment end point, which can cause doubts and uncertainty in the mind of the patient. Furthermore, it remains a significant financial burden for the patient. Herein we report our data of three patients who were reluctant for further re-injections of anti-VEGF agents and were therefore offered surgical removal of the CNVM by submacular surgery as an alternative treatment plan.

  18. Application of anti-vascular endothelial growth factor on the treatment of neovascular glaucoma

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    Ping Wu

    2015-11-01

    Full Text Available Neovascular glaucoma(NVGis a common secondary glaucoma, often occurs secondary to diabetic retinopathy, central retinal vein occlusion and retinal ischemia syndrome. Its pathogenesis is complicated. Though conventional treatmentscan brieflyreduce elevated intraocular pressure, degenerate iris neovascularization, the long-term effect for controlling NVG is not obvious. The treatment of NVG ushers in a new dawn with the in-depth study on the pathogenesis of NVG and the use of vascular endothelial growth factor(VEGFinhibitors in ophthalmic diseases. In this paper, the applications of VEGF inhibitors on the treatment of neovascular glaucoma are reviewed to provide new thoughts for the treatment of NVG.

  19. Vascular endothelial dysfunction in β-thalassemia occurs despite increased eNOS expression and preserved vascular smooth muscle cell reactivity to NO.

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    Ekatherina Stoyanova

    Full Text Available AIMS: The hereditary β-thalassemia major condition requires regular lifelong blood transfusions. Transfusion-related iron overloading has been associated with the onset of cardiovascular complications, including cardiac dysfunction and vascular anomalies. By using an untransfused murine model of β-thalassemia major, we tested the hypothesis that vascular endothelial dysfunction, alterations of arterial structure and of its mechanical properties would occur despite the absence of treatments. METHODS AND RESULTS: Vascular function and structure were evaluated ex vivo. Compared to the controls, endothelium-dependent vasodilation with acetylcholine was blunted in mesenteric resistance arteries of β-thalassemic mice while the endothelium-independent vasodilator (sodium nitroprusside produced comparable vessel dilation, indicating endothelial cell impairment with preserved smooth muscle cell reactivity to nitric oxide (NO. While these findings suggest a decrease in NO bioavailability, Western blotting showed heightened expression of aortic endothelial NO synthase (eNOS in β-thalassemia. Vascular remodeling of the common carotid arteries revealed increased medial elastin content. Under isobaric conditions, the carotid arteries of β-thalassemic mice exhibited decreased wall stress and softening due to structural changes of the vessel wall. CONCLUSIONS: A complex vasculopathy was identified in untransfused β-thalassemic mice characterized by altered carotid artery structure and endothelial dysfunction of resistance arterioles, likely attributable to reduced NO bioavailability despite enhanced vascular eNOS expression.

  20. In vitro effects of waterpipe smoke condensate on endothelial cell function: a potential risk factor for vascular disease.

    Science.gov (United States)

    Rammah, Mayyasa; Dandachi, Farah; Salman, Rola; Shihadeh, Alan; El-Sabban, Marwan

    2013-05-23

    Despite its increasing popularity, little is known about the health effects of waterpipe smoking (WPS), particularly on the cardiovascular system. To investigate the role of WPS as a risk factor for vascular disease, we evaluated its effect on endothelial cell function, which is an early event in vascular disease pathogenesis. We assessed the changes in cell viability, ROS generation, inflammatory and vasodilatory markers and in vitro angiogenesis of human aortic endothelial cells in response to waterpipe smoke condensate exposure. Mainstream waterpipe smoke condensate (WSC) was generated using a standard laboratory machine protocol. Compared to control, WSC induced cell cycle arrest, apoptosis, and oxidative stress in human primary endothelial cells. In addition, we assayed for impaired endothelium-dependent vasodilation and induced inflammation by studying the effect of WPS on the content and activity of AMPK, eNOS proteins and NF-κB p65 ser536 phosphorylation, respectively. WSC inhibited AMPK/eNOS phosphorylation and induced phosphorylation of p65. Moreover, we evaluated endothelial cells repair mechanism related properties that include migration/invasion and in vitro tube formation upon treatment with WSC. WSC reduced the motility and inhibited angiogenic potential of HAEC cells. WPS induced endothelial cell dysfunction as evident by exerting oxidative stress, inflammation, and impaired endothelial vasodilatory function and repair mechanisms. All together these data provide evidence for the potential contribution of WPS to endothelial dysfunction and thus to vascular disease. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  1. Activation of AP-1 Transcription Factors Differentiates FGF2 and Vascular Endothelial Growth Factor Regulation of Endothelial Nitric-oxide Synthase Expression in Placental Artery Endothelial Cells*

    Science.gov (United States)

    Mata-Greenwood, Eugenia; Liao, Wu-xiang; Wang, Wen; Zheng, Jing; Chen, Dong-bao

    2010-01-01

    FGF2 (fibroblast growth factor 2), but not vascular endothelial growth factor (VEGF), stimulates sustained activation of ERK2/1 for endothelial NOS3 (nitric-oxide synthase 3) protein expression in ovine fetoplacental artery endothelial cells (oFPAEC). We deciphered herein the downstream signaling of ERK2/1 responsible for NOS3 expression by FGF2 in oFPAEC. FGF2, but not VEGF, increased NOS3 mRNA levels without altering its degradation. FGF2, but not VEGF, trans-activated sheep NOS3 promoter, and this was dependent on ERK2/1 activation. FGF2 did not trans-activate NOS3 promoters with deletions upstream of the consensus AP-1 site (TGAGTC A, −678 to −685). Trans-activation of wild-type NOS3 promoter by FGF2 was significantly inhibited when either the AP-1 or the cAMP-response element (CRE)-like sequence (TGCGTCA, −752 to −758) was mutated and was completely blocked when both were mutated. EMSA analyses showed that FGF2, but not VEGF, stimulated AP-1 and CRE DNA-protein complexes primarily composed of JunB and Fra1. Chromatin immunoprecipitation assays confirmed JunB/Fra1 binding to NOS3 promoter AP-1 and CRE elements in intact cells. FGF2, but not VEGF, stimulated JunB and Fra1 expressions; all preceded NOS3 up-regulation and were inhibited by PD98059. Down-regulation of JunB or Fra-1, but not c-Jun, blocked FGF2 stimulation of NOS3 expression and NO production. AP-1 inhibition suppressed FGF2 stimulation of NOS3 expression in human umbilical vein EC and uterine artery endothelial cells. Thus, FGF2 induction of NOS3 expression is mainly mediated by AP-1-dependent transcription involving JunB and Fra1 up-regulation via sustained ERK2/1 activation in endothelial cells. PMID:20371606

  2. [Effect of cryotherapy over the expression of vascular endothelial growth factor and pigment epithelium-derived factor].

    Science.gov (United States)

    Toscano-Garibay, Julia Dolores; Quiroz-Mercado, Hugo; Espitia-Pinzón, Clara; Gil-Carrasco, Félix; Flores-Estrada, José Javier

    2014-01-01

    Cryotherapy is a no invasive technique that uses intense cold to freeze and destroy cancer tissues. There are no descriptions of its effects over the expression of vascular endothelial growth factor and pigment epithelium-derived factor. Experimental study in cryogenic spot were applied in the right sclera of twelve pigs for ten minutes. Other 3 pigs were used as normal controls. Animals were sacrificed at 7, 14 and 21 and the tissues of choriodes and retina were dissected in areas of approximately 1 cm2 surrounding cryogenic spots. Expression levels of vascular endothelial growth factor and pigment epithelium-derived factor were determined analyzed using polymerase chain reaction coupled to reverse-transcription. Vascular endothelial growth factor was significantly downregulated (24%, p< 0.05) seven days post-treatment meanwhile pigment epithelium-derived factor levels increased 44.8% (p< 0.05) as compared to normal controls (untreated). Both vascular endothelial growth factor and pigment epithelium-derived factor levels remain the same until day 14 but returned to basal expression at day 21. This work expose the relation of cryotherapy with the expression of two factors related to angiogenesis. RESULTS showed significant changes on the expression of vascular endothelial growth factor and pigment epithelium-derived factor illustrating that both proteins are regulated in response to cryogenic treatment in relatively short periods (21 days).

  3. Vascular Endothelial Growth Factor Levels in Dobrava/Belgrade Virus Infections

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    Katerina Tsergouli

    2013-12-01

    Full Text Available The levels of vascular endothelial growth factor-A (VEGF were estimated in 102 serum samples from 63 hospitalized Greek patients with hemorrhagic fever with renal syndrome (HFRS caused by Dobrava/Belgrade virus. Significantly higher VEGF levels were seen in the severe when compared with non-severe cases (mean values 851.96 pg/mL and 326.75 pg/mL, respectively; p = 0.003, while a significant difference was observed among groups based on the day after the onset of illness. In both severe and non-severe cases, VEGF peaked in the second week of illness; however, elevation of VEGF in the severe cases started later and remained high until convalescence, suggesting that the role of VEGF was associated with repair of vascular damage rather than with increased permeability.

  4. Vascular endothelial growth factor levels in dobrava/belgrade virus infections.

    Science.gov (United States)

    Tsergouli, Katerina; Papa, Anna

    2013-12-10

    The levels of vascular endothelial growth factor-A (VEGF) were estimated in 102 serum samples from 63 hospitalized Greek patients with hemorrhagic fever with renal syndrome (HFRS) caused by Dobrava/Belgrade virus. Significantly higher VEGF levels were seen in the severe when compared with non-severe cases (mean values 851.96 pg/mL and 326.75 pg/mL, respectively; p = 0.003), while a significant difference was observed among groups based on the day after the onset of illness. In both severe and non-severe cases, VEGF peaked in the second week of illness; however, elevation of VEGF in the severe cases started later and remained high until convalescence, suggesting that the role of VEGF was associated with repair of vascular damage rather than with increased permeability.

  5. Protection against vascular endothelial dysfunction by polyphenols in sea buckthorn berries in rats with hyperlipidemia.

    Science.gov (United States)

    Yang, Fang; Suo, Yourui; Chen, Dongli; Tong, Li

    2016-07-19

    Chronic hyperlipemia increases the incidence of vascular endothelial dysfunction and can even induce cardiovascular disease. Sea buckthorn contains a host of bioactives such as flavonoids and polyphenols that can prevent the development of cardiovascular disease. The current study isolated active ingredients, polyphenols, from sea buckthorn berries (SVP) and orally administered SVP at a dose of 7-28 mg/kg. This treatment significantly reduced serum lipids, it enhanced the activity of antioxidant enzymes, and it decreased the level of serum TNF-α and IL-6. SVP also alleviate vascular impairment by decreasing the expression of eNOS, ICAM-1, and LOX-1 mRNA and proteins in aortas of rats with hyperlipidemia. Based on these findings, SVP has antioxidant action and it protects endothelium.

  6. Analysis of p53 and vascular endothelial growth factor expression in human gallbladder carcinoma for the determination of tumor vascularity

    Institute of Scientific and Technical Information of China (English)

    Yu Tian; Ren-Yu Ding; Ying-Hui Zhi; Ren-Xuan Guo; Shuo-Dong Wu

    2006-01-01

    AIM: To examine the expression of p53 and vascular endothelial growth factor (VEGF) as well as microvessel count (MVC) and to investigate the role of VEGF as an angiogenic marker and the possible role of p53 in the regulation of angiogenesis in human gallbladder carcinoma.METHODS: Surgically resected specimens of 49 gallbladder carcinomas were studied by immunohistochemical staining for p53 protein, VEGF, and factor Ⅷ-related antigen. VEGF expression and mutant p53 expression were then correlated with Nevin stage,differentiation grade, MVC, and lymph node metastasis.RESULTS: Positive p53 protein and VEGF expressions were found in 61.2% and 63.3% of tumors, respectively.p53 and VEGF staining status was identical in 55.1%of tumors. The Nevin staging of p53- or VEGF-positive tumors was significantly later than that of negative tumors. The MVC in p53- or VEGF-positive tumors was significantly higher than that in negative tumors,and MVC in both p53- and VEGF-negative tumors was significantly lower than that in the other subgroups.CONCLUSION: Our findings suggest that p53-VEGF pathway can regulate tumor angiogenesis in human gallbladder carcinoma. Combined analysis of p53 and VEGF expression might be useful for predicting the tumor vascularity of gallbladder cancer.

  7. Euterpe oleracea Mart. extract prevents vascular remodeling and endothelial dysfunction in spontaneously hypertensive rats

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    Viviane Silva Cristino Cordeiro

    2015-06-01

    Full Text Available Summary. We assessed the effects of Euterpe oleracea Mart. (açaí seed extract (ASE rich in proanthocyanidins and catechin on vascular dysfunction and oxidative stress associated with hypertension in spontaneously hypertensive rats (SHR. SHR and control rats were treated with ASE (200 mg/kg/day or vehicle for 10 weeks. In the rat mesenteric arterial bed (MAB, acetylcholine response, endothelial nitric oxide synthase (eNOS and superoxide dismutase 1 (SOD 1 expressions were studied. The antioxidant enzyme activity, oxidative damage and nitrite quantification were assessed in MAB and heart homogenates. eNOS immunohistochemistry and histological analysis was carried out on aortic sections. ASE was able to attenuate the hypertension and prevent the endothelial dysfunction in MAB of SHR. The increased levels of protein carbonylation and associated low levels of nitrite in MAB and heart of SHR were attenuated by ASE. The up-regulation of eNOS and SOD1 expression and the increased activity of SOD in MAB from SHR were normalized by ASE. In aorta from SHR, ASE prevented the increase in media thickness, media:lumen ratio and the decrease in the percentage of elastic fibers. Our results suggest that ASE produces antihypertensive effect and prevents the vascular dysfunction in SHR, through mechanisms involving antioxidant effects and NO production. Industrial relevance. Euterpe oleracea Mart. (Açaí has been considered one of the most important medicinal plants of the Amazon by its beneficial effects in the treatment of fever, pain, inflammation and anemia. More recently, Euterpe oleracea Mart. has been reported to reduce blood pressure with an important antioxidant property. The present research reports the protective effect of the extract of the seeds from Euterpe oleraca Mart. against high blood pressure and the associated vascular structural and functional changes. The test for antihypertensive and vascular anti-hypertrophic effect of the hydro

  8. The defensive effect of benfotiamine in sodium arsenite-induced experimental vascular endothelial dysfunction.

    Science.gov (United States)

    Verma, Sanjali; Reddy, Krishna; Balakumar, Pitchai

    2010-10-01

    The present study has been designed to investigate the effect of benfotiamine, a thiamine derivative, in sodium arsenite-induced vascular endothelial dysfunction (VED) in rats. Sodium arsenite (1.5 mg(-1) kg(-1) day(-1) i.p., 2 weeks) was administered in rats to produce VED. The development of VED was assessed by employing isolated aortic ring preparation and estimating the serum and aortic concentrations of nitrite/nitrate. Further, the integrity of vascular endothelium in thoracic aorta was assessed by scanning electron microscopy. Moreover, the oxidative stress was assessed by estimating serum thiobarbituric acid reactive substances (TBARS) and aortic superoxide anion generation. The administration of sodium arsenite markedly produced VED by attenuating acetylcholine-induced endothelium-dependent relaxation, decreasing serum and aortic concentrations of nitrite/nitrate, and impairing the integrity of vascular endothelium. Further, sodium arsenite produced oxidative stress by increasing serum TBARS and aortic superoxide generation. The treatment with benfotiamine (25, 50, and 100 mg(-1) kg(-1) day(-1) p.o.) or atorvastatin (30 mg(-1) kg(-1) day(-1) p.o., a standard agent) prevented sodium arsenite-induced VED and oxidative stress. However, the beneficial effects of benfotiamine in preventing the sodium arsenite-induced VED were attenuated by co-administration with N-omega-nitro-L: -arginine methyl ester (L: -NAME) (25 mg(-1) kg(-1) day(-1), i.p.), an inhibitor of NOS. Thus, it may be concluded that benfotiamine reduces oxidative stress and activates endothelial nitric oxide synthase to enhance the generation and bioavailability of NO and subsequently improves the integrity of vascular endothelium to prevent sodium arsenite-induced experimental VED.

  9. Knockout of the vascular endothelial glucocorticoid receptor abrogates dexamethasone-induced hypertension

    Science.gov (United States)

    GOODWIN, Julie E.; ZHANG, Junhui; GONZALEZ, David; ALBINSSON, Sebastian; GELLER, David S.

    2012-01-01

    Glucocorticoid-mediated hypertension is incompletely understood. Recent studies have suggested the primary mechanism of this form of hypertension may be through the effects of glucocorticoids on vascular tissues and not to excess sodium and water reabsorption as traditionally believed. Objective The goal of this study was to better understand the role of the vasculature in the generation and maintenance of glucocorticoid-mediated hypertension. Methods We created a mouse model with a tissue-specific knockout of the glucocorticoid receptor in the vascular endothelium. Results We show that these mice are relatively resistant to dexamethasone-induced hypertension. After one week of dexamethasone treatment, control animals have a mean blood pressure increase of 13.1 mm Hg while knockout animals have only a 2.7 mm Hg increase (p<0.001). Interestingly, the knockout mice have slightly elevated baseline BP compared to the controls (112.2 ± 2.5 mm Hg vs. 104.6 ± 1.2 mm Hg, p = 0.04), a finding which is not entirely explained by our data. Furthermore, we demonstrate that the knockout resistance arterioles have a decreased contractile response to dexamethasone with only 6.6% contraction in knockout vessels compared to 13.4% contraction in control vessels (p=0.034). Finally, we show that in contrast to control animals, the knockout animals are able to recover a significant portion of their normal circadian blood pressure rhythm suggesting that the vascular endothelial glucocorticoid receptor may function as a peripheral circadian clock. Conclusions Our study highlights the importance of the vascular endothelial GR in several fundamental physiologic processes, namely blood pressure homeostasis and circadian rhythm. PMID:21659825

  10. Angiotensin II-Induced Endothelial Dysfunction is Temporally Linked with Increases in Intereukin-6 and Vascular Macrophage Accumulation

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    Sean P Didion

    2014-10-01

    Full Text Available Angiotensin II (Ang II is associated with vascular hypertrophy, endothelial dysfunction and activation of a number of inflammatory molecules, however the linear events involved in the development of hypertension and endothelial dysfunction produced in response to Ang II are not well defined. The goal of this study was to examine the dose- and temporal-dependent development of endothelial dysfunction in response to Ang II. Blood pressure and responses of carotid arteries were examined in control (C57Bl/6 mice and in mice infused with 50, 100, 200, 400, or 1000 ng/kg/min Ang II for either 14 or 28 Days. Infusion of Ang II was associated with graded and marked increases in systolic blood pressure and plasma Ang II concentrations. While low doses of Ang II (ie, 50 and 100 ng/kg/min had little to no effect on blood pressure or endothelial function, high doses of Ang II (e.g., 1000 ng/kg/min were associated with large increases in arterial pressure and marked impairment of endothelial function. In contrast, intermediate doses of Ang II (200 and 400 ng/kg/min while initially having no effect on systolic blood pressure were associated with significant increases in pressure over time. Despite increasing blood pressure, 200 ng/kg/min had no effect on endothelial function, whereas 400 ng/kg/min produced modest impairment on Day 14 and marked impairment of endothelial function on Day 28. The degree of endothelial dysfunction produced by 400 and 1000 ng/kg/min Ang II was reflective of parallel increases in plasma IL-6 levels and vascular macrophage content, suggesting that increases in arterial blood pressure precede the development of endothelial dysfunction. These findings are important as they demonstrate that along with increases in arterial pressure that increases in IL-6 and vascular macrophage accumulation correlate with the impairment of endothelial function produced by Ang II.

  11. F-actin-rich contractile endothelial pores prevent vascular leakage during leukocyte diapedesis through local RhoA signalling.

    Science.gov (United States)

    Heemskerk, Niels; Schimmel, Lilian; Oort, Chantal; van Rijssel, Jos; Yin, Taofei; Ma, Bin; van Unen, Jakobus; Pitter, Bettina; Huveneers, Stephan; Goedhart, Joachim; Wu, Yi; Montanez, Eloi; Woodfin, Abigail; van Buul, Jaap D

    2016-01-27

    During immune surveillance and inflammation, leukocytes exit the vasculature through transient openings in the endothelium without causing plasma leakage. However, the exact mechanisms behind this intriguing phenomenon are still unknown. Here we report that maintenance of endothelial barrier integrity during leukocyte diapedesis requires local endothelial RhoA cycling. Endothelial RhoA depletion in vitro or Rho inhibition in vivo provokes neutrophil-induced vascular leakage that manifests during the physical movement of neutrophils through the endothelial layer. Local RhoA activation initiates the formation of contractile F-actin structures that surround emigrating neutrophils. These structures that surround neutrophil-induced endothelial pores prevent plasma leakage through actomyosin-based pore confinement. Mechanistically, we found that the initiation of RhoA activity involves ICAM-1 and the Rho GEFs Ect2 and LARG. In addition, regulation of actomyosin-based endothelial pore confinement involves ROCK2b, but not ROCK1. Thus, endothelial cells assemble RhoA-controlled contractile F-actin structures around endothelial pores that prevent vascular leakage during leukocyte extravasation.

  12. Increased expression of the sonic hedgehog and vascular endothelial growth factor with co-localization in varicocele veins.

    Science.gov (United States)

    Wang, Shih-Ho; Yang, Wen-Kai; Lee, Jane-Dar

    2017-03-01

    Objectives Varicocele is characterized by dilatation and tortuosity of the internal spermatic vein. Sonic hedgehog plays an important role in angiogenesis and vascular remodeling under hypoxic stress. We studied the relationship and distribution of SHH and vascular endothelial growth factor in internal spermatic vein in patients diagnosed with varicocele. Methods Specimens of 1 cm were taken from the internal spermatic vein during left varicocele repair (N = 20). The control samples of ISV were obtained from eight male patients who underwent left inguinal herniorrhaphy. We analyzed the sonic hedgehog and vascular endothelial growth factor expression and distribution by immunoblotting, immunohistochemistry, immunofluorescent staining, and confocal laser scanning microscopy. The data were analyzed using the Student's t test. Results Immunoblotting showed higher expression of sonic hedgehog and vascular endothelial growth factor proteins in varicocele veins than in the control group ( P sonic hedgehog and vascular endothelial growth factor with co-localization in varicocele veins which imply that the reducing hypoxia or using sonic hedgehog antagonists may be helpful for this vascular disease.

  13. Microparticles generated during chronic cerebral ischemia deliver proapoptotic signals to cultured endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Schock, Sarah C. [Ottawa Hospital Research Institute, Neuroscience, 451 Smyth Road, Ottawa, ON K1H 8M5 (Canada); Edrissi, Hamidreza [University of Ottawa, Neuroscience Graduate Program, 451 Smyth Road, Ottawa, ON K1H 8M5 (Canada); Burger, Dylan [Ottawa Hospital Research Institute, Kidney Centre, 451 Smyth Road, Ottawa, ON K1H 8M5 (Canada); Cadonic, Robert; Hakim, Antoine [Ottawa Hospital Research Institute, Neuroscience, 451 Smyth Road, Ottawa, ON K1H 8M5 (Canada); Thompson, Charlie, E-mail: charliet@uottawa.ca [Ottawa Hospital Research Institute, Neuroscience, 451 Smyth Road, Ottawa, ON K1H 8M5 (Canada)

    2014-07-18

    Highlights: • Microparticles are elevated in the plasma in a rodent model of chronic cerebral ischemia. • These microparticles initiate apoptosis in cultured cells. • Microparticles contain caspase 3 and they activate receptors for TNF-α and TRAIL. - Abstract: Circulating microparticles (MPs) are involved in many physiological processes and numbers are increased in a variety of cardiovascular disorders. The present aims were to characterize levels of MPs in a rodent model of chronic cerebral hypoperfusion (CCH) and to determine their signaling properties. MPs were isolated from the plasma of rats exposed to CCH and quantified by flow cytometry. When MPs were added to cultured endothelial cells or normal rat kidney cells they induced cell death in a time and dose dependent manner. Analysis of pellets by electron microscopy indicates that cell death signals are carried by particles in the range of 400 nm in diameter or less. Cell death involved the activation of caspase 3 and was not a consequence of oxidative stress. Inhibition of the Fas/FasL signaling pathway also did not improve cell survival. MPs were found to contain caspase 3 and treating the MPs with a caspase 3 inhibitor significantly reduced cell death. A TNF-α receptor blocker and a TRAIL neutralizing antibody also significantly reduced cell death. Levels of circulating MPs are elevated in a rodent model of chronic cerebral ischemia. MPs with a diameter of 400 nm or less activate the TNF-α and TRAIL signaling pathways and may deliver caspase 3 to cultured cells.

  14. Characterization of nicardipine hydrochloride-induced cell injury in human vascular endothelial cells.

    Science.gov (United States)

    Ochi, Masanori; Kawai, Yoshiko; Tanaka, Yoshiyuki; Toyoda, Hiromu

    2015-02-01

    Nicardipine hydrochloride (NIC), a dihydropyridine calcium-channel blocking agent, has been widely used for the treatment of hypertension. Especially, nicardipine hydrochloride injection is used as first-line therapy for emergency treatment of abnormally high blood pressure. Although NIC has an attractive pharmacological profile, one of the dose-limiting factors of NIC is severe peripheral vascular injury after intravenous injection. The goal of this study was to better understand and thereby reduce NIC-mediated vascular injury. Here, we investigated the mechanism of NIC-induced vascular injury using human dermal microvascular endothelial cells (HMVECs). NIC decreased cell viability and increased percent of dead cells in a dose-dependent manner (10-30 μg/mL). Although cell membrane injury was not significant over 9 hr exposure, significant changes of cell morphology and increases in vacuoles in HMVECs were observed within 30 min of NIC exposure (30 μg/mL). Autophagosome labeling with monodansylcadaverine revealed increased autophagosomes in the NIC-treated cells, whereas caspase 3/7 activity was not increased in the NIC-treated cells (30 μg/mL). Additionally, NIC-induced reduction of cell viability was inhibited by 3-methyladenine, an inhibitor of autophagosome formation. These findings suggest that NIC causes severe peripheral venous irritation via induction of autophagic cell death and that inhibition of autophagy could contribute to the reduction of NIC-induced vascular injury.

  15. TRAF6 inhibits proangiogenic signals in endothelial cells and regulates the expression of vascular endothelial growth factor

    Energy Technology Data Exchange (ETDEWEB)

    Bruneau, Sarah; Datta, Dipak; Flaxenburg, Jesse A.; Pal, Soumitro [Transplantation Research Center, Division of Nephrology, Department of Medicine, Children' s Hospital Boston, Boston, MA (United States); Department of Pediatrics, Harvard Medical School, Boston, MA (United States); Briscoe, David M., E-mail: david.briscoe@childrens.harvard.edu [Transplantation Research Center, Division of Nephrology, Department of Medicine, Children' s Hospital Boston, Boston, MA (United States); Department of Pediatrics, Harvard Medical School, Boston, MA (United States)

    2012-03-02

    Highlights: Black-Right-Pointing-Pointer TNF-receptor associated factors (TRAFs) function in the angiogenesis response. Black-Right-Pointing-Pointer TRAF6 regulates basal and inducible expression of VEGF in endothelial cells (EC). Black-Right-Pointing-Pointer TRAF6 is an endogenous inhibitor of EC proliferation and migration in EC. Black-Right-Pointing-Pointer TRAF6 inhibits VEGF expression in part via its ability to regulate Src signaling. -- Abstract: TNF-family molecules induce the expression Vascular Endothelial Growth Factor (VEGF) in endothelial cells (EC) and elicit signaling responses that result in angiogenesis. However, the role of TNF-receptor associated factors (TRAFs) as upstream regulators of VEGF expression or as mediators of angiogenesis is not known. In this study, HUVEC were cotransfected with a full-length VEGF promoter-luciferase construct and siRNAs to TRAF 1, -2, -3, -5, -6, and promoter activity was measured. Paradoxically, rather than inhibiting VEGF expression, we found that knockdown of TRAF6 resulted in a 4-6-fold increase in basal VEGF promoter activity compared to control siRNA-transfected EC (P < 0.0001). In addition, knockdown of TRAF 1, -2, -3 or -5 resulted in a slight increase or no change in VEGF promoter activation. Using [{sup 3}H]thymidine incorporation assays as well as the in vitro wound healing assay, we also found that basal rates of EC proliferation and migration were increased following TRAF6 knockdown; and this response was inhibited by the addition of a blocking anti-VEGF antibody into cell cultures. Using a limited protein array to gain insight into TRAF6-dependent intermediary signaling responses, we observed that TRAF6 knockdown resulted in an increase in the activity of Src family kinases. In addition, we found that treatment with AZD-0530, a pharmacological Src inhibitor, reduced the regulatory effect of TRAF6 knockdown on VEGF promoter activity. Collectively, these findings define a novel pro-angiogenic signaling

  16. Deregulation of Flk-1/vascular endothelial growth factor receptor-2 in fibroblast growth factor receptor-1-deficient vascular stem cell development.

    Science.gov (United States)

    Magnusson, Peetra; Rolny, Charlotte; Jakobsson, Lars; Wikner, Charlotte; Wu, Yan; Hicklin, Daniel J; Claesson-Welsh, Lena

    2004-03-15

    We have employed embryoid bodies derived from murine embryonal stem cells to study effects on vascular development induced by fibroblast growth factor (FGF)-2 and FGF receptor-1, in comparison to the established angiogenic factor vascular endothelial growth factor (VEGF)-A and its receptor VEGF receptor-2. Exogenous FGF-2 promoted formation of morphologically distinct, long slender vessels in the embryoid bodies, whereas VEGF-A-treated bodies displayed a compact plexus of capillaries. FGF-2 stimulation of embryonal stem cells under conditions where VEGF-A/VEGFR-2 function was blocked, led to formation of endothelial cell clusters, which failed to develop into vessels. FGFR-1(-/-) embryoid bodies responded to VEGF-A by establishment of the characteristic vascular plexus, but FGF-2 had no effect on vascular development in the absence of FGFR-1. The FGFR-1(-/-) embryoid bodies displayed considerably increased basal level of vessel formation, detected by immunohistochemical staining for platelet-endothelial cell adhesion molecule (PECAM)/CD31. This basal vascularization was blocked by neutralizing antibodies against VEGFR-2 or VEGF-A and biochemical analyses indicated changes in regulation of VEGFR-2 in the absence of FGFR-1 expression. We conclude that VEGF-A/VEGFR-2-dependent vessel formation occurs in the absence of FGF-2/FGFR-1, which, however, serve to modulate vascular development.

  17. Vascular endothelial growth factor (VEGF), produced by feline infectious peritonitis (FIP) virus-infected monocytes and macrophages, induces vascular permeability and effusion in cats with FIP.

    Science.gov (United States)

    Takano, Tomomi; Ohyama, Taku; Kokumoto, Aiko; Satoh, Ryoichi; Hohdatsu, Tsutomu

    2011-06-01

    Feline infectious peritonitis virus (FIPV) causes a fatal disease called FIP in Felidae. The effusion in body cavity is commonly associated with FIP. However, the exact mechanism of accumulation of effusion remains unclear. We investigated vascular endothelial growth factor (VEGF) to examine the relationship between VEGF levels and the amounts of effusion in cats with FIP. Furthermore, we examined VEGF production in FIPV-infected monocytes/macrophages, and we used feline vascular endothelial cells to examine vascular permeability induced by the culture supernatant of FIPV-infected macrophages. In cats with FIP, the production of effusion was related with increasing plasma VEGF levels. In FIPV-infected monocytes/macrophages, the production of VEGF was associated with proliferation of virus. Furthermore, the culture supernatant of FIPV-infected macrophages induced hyperpermeability of feline vascular endothelial cells. It was suggested that vascular permeability factors, including VEGF, produced by FIPV-infected monocytes/macrophages might increase the vascular permeability and the amounts of effusion in cats with FIP.

  18. Additive effect of red blood cell rigidity and adherence to endothelial cells in inducing vascular resistance.

    Science.gov (United States)

    Kaul, D K; Koshkaryev, A; Artmann, G; Barshtein, G; Yedgar, S

    2008-10-01

    To explore the contribution of red blood cell (RBC) deformability and interaction with endothelial cells (ECs) to circulatory disorders, these RBC properties were modified by treatment with hydrogen peroxide (H(2)O(2)), and their effects on vascular resistance were monitored following their infusion into rat mesocecum vasculature. Treatment with 0.5 mM H(2)O(2) increased RBC/EC adherence without significant alteration of RBC deformability. At 5.0 mM H(2)O(2), RBC deformability was considerably reduced, inducing a threefold increase in the number of undeformable cells, whereas RBC/EC adherence was not further affected by the increased H(2)O(2) concentration. This enabled the selective manipulation of RBC adherence and deformability and the testing of their differential effect on vascular resistance. Perfusion of RBCs with enhanced adherence and unchanged deformability (treatment with 0.5 mM H(2)O(2)) increased vascular resistance by about 35% compared with untreated control RBCs. Perfusion of 5.0 mM H(2)O(2)-treated RBCs, with reduced deformability (without additional increase of adherence), further increased vascular resistance by about 60% compared with untreated control RBCs. These results demonstrate the specific effects of elevated adherence and reduced deformability of oxidized RBCs on vascular resistance. These effects can be additive, depending on the oxidation conditions. The oxidation-induced changes applied in this study are moderate compared with those observed in RBCs in pathological states. Yet, they caused a considerable increase in vascular resistance, thus demonstrating the potency of RBC/EC adherence and RBC deformability in determining resistance to blood flow in vivo.

  19. Interactive effects of vascular risk burden and advanced age on cerebral blood flow

    Directory of Open Access Journals (Sweden)

    Katherine eBangen

    2014-07-01

    Full Text Available Vascular risk factors and cerebral blood flow (CBF reduction have been linked to increased risk of cognitive impairment and Alzheimer’s disease (AD; however the possible moderating effects of age and vascular risk burden on CBF in late life remain understudied. We examined the relationships among elevated vascular risk burden, age, CBF, and cognition. Seventy-one non-demented older adults completed an arterial spin labeling MR scan, neuropsychological assessment, and medical history interview. Relationships among vascular risk burden, age, and CBF were examined in a priori regions of interest (ROIs previously implicated in aging and AD. Interaction effects indicated that, among older adults with elevated vascular risk burden (i.e., multiple vascular risk factors, advancing age was significantly associated with reduced cortical CBF whereas there was no such relationship for those with low vascular risk burden (i.e., no or one vascular risk factor. This pattern was observed in cortical ROIs including medial temporal (hippocampus, parahippocampal gyrus, uncus, inferior parietal (supramarginal gyrus, inferior parietal lobule, angular gyrus, and frontal (anterior cingulate, middle frontal gyrus, medial frontal gyrus cortices. Furthermore, among those with elevated vascular risk, reduced CBF was associated with poorer cognitive performance. Such findings suggest that older adults with elevated vascular risk burden may be particularly vulnerable to cognitive change as a function of CBF reductions. Findings support the use of CBF as a potential biomarker in preclinical AD and suggest that vascular risk burden and regionally-specific CBF changes may contribute to differential age-related cognitive declines.

  20. Effect of arsenic trioxide on vascular endothelial cell proliferation and expression of vascular endothelial growth factor receptors Flt-1 and KDR in gastric cancer in nude mice

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To investigate the effect of arsenic trioxide (As2O3) on expression of vascular endothelial growth factor receptor-1 (VEGFR-1, Flt-1) and VEGFR-2 (KDR) in human gastric tumor cells and proliferation of vascular endothelial cells.METHODS: The solid tumor model was formed in nude mice with the gastric cancer cell line SGC-7901. The animals were treated with As2O3. Microvessel density (MVD) and expression of Flt-1 and KDR were detected by immunofluorescence laser confocal microscopy.SGC-7901 cells were treated respectively by exogenous recombinant human VEGF165 or VEGF165 + As2O3. Cell viability was measured by MTT assay. Cell viability of ECV304 cells was measured by MTT assay, and cell cycle and apoptosis were analyzed using flow cytometry.RESULTS: The tumor growth inhibition was 30.33% and 50.85%, respectively, in mice treated with As2O3 2.5 and 5 mg/kg. MVD was significantly lower in arsenic-treated mice than in the control group. The fluorescence intensity levels of Flt-1 and KDR were significantly less in the arsenic-treated mice than in the control group. VEGF165 may accelerate growth of SGC7901 cells, but As2O3 may disturb the stimulating effect of VEGF165. ECV304 cell growth was suppressed by 76.51%, 71.09% and 61.49% after 48 h treatment with As2O3 at 0.5, 2.5 and 5 μmol/L, respectively. Early apoptosis in the As2O3-treated mice was 2.88-5.1 times higher than that in the controls, and late apoptosis was 1.17-1.67 times higher than that in the controls.CONCLUSION: Our results showed that As2O3 delays tumor growth, inhibits MVD, down-regulates Flt-1 and KDR expression, and disturbs the stimulating effect of VEGF165 on the growth of SGC7901 cells. These results suggest that As2O3 might delay growth of gastric tumors through inhibiting the paracrine and autocrine pathways of VEGF/VEGFRs.

  1. Cerebral cavernous malformations as a disease of vascular permeability: from bench to bedside with caution.

    Science.gov (United States)

    Yadla, Sanjay; Jabbour, Pascal M; Shenkar, Robert; Shi, Changbin; Campbell, Peter G; Awad, Issam A

    2010-09-01

    Tremendous insight into the molecular and genetic pathogenesis of cerebral cavernous malformations (CCMs) has been gained over the past 2 decades. This includes the identification of 3 distinct genes involved in familial CCMs. Still, a number of unanswered questions regarding the process from gene mutation to vascular malformation remain. It is becoming more evident that the disruption of interendothelial junctions and ensuing vascular hyperpermeability play a principal role. The purpose of this review is to summarize the current understanding of CCM genes, associated proteins, and functional pathways. Promising molecular and genetic therapies targeted at identified molecular aberrations are discussed as well.

  2. Effect of Carvedilol on the Coronary Vascular Endothelial Function after Percutaneous Transluminal Coronary Angioplasty

    Institute of Scientific and Technical Information of China (English)

    苏显明; 马奕; 崔长琮

    2003-01-01

    Objectives To understand the effect of carvedilol on the coronary vascular endothelial function of the patients with coronary heart disease after percutaneous transluminal coronary angioplasty (PTCA). Methods 51cases, having one or more than two branches narrow ( ≥ 70% ) , were diagnosed by coronary angiography. These patients were divided randomly into carvedilol group (n = 28 ) and control group (n = 23) who did not take carvedilol.Endothelin (ET) and nitro dioxide (NO) levels of peripheral blood were measured before and after PTCA,before and after two weeks by taking carvedilol. Results Compared with the ET and NO levels before PTCA, ET were markedly increased and NO were decreased after PTCA (p < 0.05); compared with the ET and NO levels before taking carvedilol, ET were decreased and NO were increased after two week (p <0.05) , but the ET and NO levels of the control group did not change in the period of two weeks observation (p > 0.05). Conclusions Carvedilol may improve the coronary vascular endothelial function after PTCA.

  3. Role of vascular endothelial growth factor and other growth factors in post-stroke recovery

    Directory of Open Access Journals (Sweden)

    Tanu Talwar

    2014-01-01

    Full Text Available Stroke is a major health problem world-wide and its burden has been rising in last few decades. Until now tissue plasminogen activator is only approved treatment for stroke. Angiogenesis plays a vital role for striatal neurogenesis after stroke. Administration of various growth factors in an early post ischemic phase, stimulate both angiogenesis and neurogenesis and lead to improved functional recovery after stroke. However vascular endothelial growth factors (VEGF is the most potent angiogenic factor for neurovascularization and neurogenesis in ischemic injury can be modulated in different ways and thus can be used as therapy in stroke. In response to the ischemic injury VEGF is released by endothelial cells through natural mechanism and leads to angiogenesis and vascularization. This release can also be up regulated by exogenous administration of Mesenchymal stem cells, by various physical therapy regimes and electroacupuncture, which further potentiate the efficacy of VEGF as therapy in post stroke recovery. Recent published literature was searched using PubMed and Google for the article reporting on methods of up regulation of VEGF and therapeutic potential of growth factors in stroke.

  4. Mobilization of endothelial precursor cells: systemic vascular response to musculoskeletal trauma.

    LENUS (Irish Health Repository)

    Laing, A J

    2012-02-03

    Postnatal vasculogenesis, the process by which vascular committed bone marrow stem cells or endothelial precursor cells (EPC) migrate, differentiate, and incorporate into the nacent endothelium contributing to physiological and pathological neovascularization, has stimulated much interest. Its contribution to tumor nonvascularization, wound healing, and revascularization associated with skeletal and cardiac muscles ischaemia is established. We evaluated the mobilization of EPCs in response to musculoskeletal trauma. Blood from patients (n = 15) following AO type 42a1 closed diaphyseal tibial fractures was analyzed for CD34 and AC133 cell surface marker expression. Immunomagnetically enriched CD34+ mononuclear cell (MNC(CD34+)) populations were cultured and examined for phenotypic and functional vascular endothelial differentiation. Circulating MNC(CD34+) levels increased sevenfold by day 3 postinjury. Circulating MNC(AC133+) increased 2.5-fold. Enriched MNC(CD34+) populations from day 3 samples in culture exhibited cell cluster formation with sprouting spindles. These cells bound UEA-1 and incorporated fluorescent DiI-Ac-LDL intracellularily. Our findings suggest a systemic provascular response is initiated in response to musculoskeletal trauma. Its therapeutic manipulation may have implications for the potential enhancement of fracture healing.

  5. Antiangiogenic mechanisms of PJ-8, a novel inhibitor of vascular endothelial growth factor receptor signaling.

    Science.gov (United States)

    Huang, Shiu-Wen; Lien, Jin-Cherng; Kuo, Sheng-Chu; Huang, Tur-Fu

    2012-05-01

    Angiogenesis occurs not only during tissue growth and development but also during wound healing and tumor progression. Angiogenesis is a balanced process controlled by proangiogenic and antiangiogenic molecules. As a critical factor in the induction of angiogenesis, vascular endothelial growth factor (VEGF) has become an attractive target for antiangiogenic and cancer therapeutic agents. In an effort to develop novel inhibitors to block VEGF signaling, we selected Pj-8, a benzimidazole derivative, and investigated its inhibitory mechanisms in human umbilical vascular endothelial cells (HUVECs). Pj-8 concentration-dependently inhibited VEGF-induced proliferation, migration and tube formation of HUVECs. Pj-8 also suppressed VEGF-induced microvessel sprouting from aortic rings ex vivo and suppressed neovascularization of implanted matrigel plugs in vivo. Pj-8 inhibited VEGF-induced phosphorylation of VEGF receptor (VEGFR) 2 and the downstream protein kinases, including Akt, focal adhesion kinase, extracellular signal-regulated kinases and Src. Results from in vitro kinase assay further demonstrated that Pj-8 suppressed the kinase activity of 3-phosphoinositide-dependent kinase 1 (PDK1). Using xenograft tumor angiogenesis model, Pj-8 markedly eliminated tumor-associated angiogenesis. Taken together, our findings suggest that Pj-8 inhibits VEGF and tumor cells MDA-MB-231-induced angiogenesis, and it may be a potential drug candidate in anticancer therapy. Downregulation of VEGFR2-mediated signaling may contribute to its antiangiogenic actions.

  6. Vascular endothelial growth factor promotes peripheral nerve regeneration after sciatic nerve transection in rat

    Directory of Open Access Journals (Sweden)

    Mohammadi Rahim

    2013-12-01

    Full Text Available 【Abstract】Objective: To evaluate the local effect of vascular endothelial growth factor (VEGF on transected sciatic nerve regeneration. Methods: Sixty male white Wistar rats were divided into four experimental groups randomly (n=15. In transected group the left sciatic nerve was transected and the stump was fixed to adjacent muscle. In treatment group the defect was bridged using a silicone graft filled with 10 µL VEGF. In silicone group the graft was filled with phosphate-buffered saline. In sham-operated group the sciatic nerve was ex- posed and manipulated. Each group was subdivided into three subgroups with five animals in each and nerve fibers were studied 4, 8 and 12 weeks after operation. Results: Behavioral test, functional study of sciatic nerve, gastrocnemius muscle mass and morphometric indi- ces confirmed a faster recovery of regenerated axons in VEGF group than in silicone group (P<0.05. In immunohistochemi- cal assessment, reactions to S-100 in VEGF group were more positive than that in silicone group. Conclusion: Local administration of VEGF will im- prove functional recovery and morphometric indices of sci- atic nerve. Key words: Peripheral nerves; Nerve regeneration; Sciatic nerve; Vascular endothelial growth factor

  7. PRIMING EFFECT OF HOMOCYSTEINE ON INDUCIBLE VASCULAR CELL ADHESION MOLECULE-1 EXPRESSION IN ENDOTHELIAL CELLS

    Science.gov (United States)

    Séguin, Chantal; Abid, Md. Ruhul; Spokes, Katherine C.; Schoots, Ivo G; Brkovic, Alexandre; Sirois, Martin G.; Aird, William C.

    2017-01-01

    Hyperhomocysteinemia is an independent risk factor for the development of atherosclerosis, as well as for arterial and venous thrombosis. However, the mechanisms through which elevated circulating levels of homocysteine cause vascular injury and promote thrombosis remain unclear. Here, we tested the hypothesis that homocysteine (Hcy) sensitizes endothelial cells to the effect of inflammatory mediators. Human umbilical vein endothelial cells (HUVEC) were incubated with Hcy 1.0 mM for varying time points, and then treated in the absence or presence of 1.5 U/ml thrombin or 10 ng/ml lipopolysaccharide (LPS). Hcy alone had no effect on the expression of vascular cell adhesion molecule (VCAM)-1. However, Hcy enhanced thrombin- and LPS-mediated induction of VCAM-1 mRNA and protein levels. Consistent with these results, pretreatment of HUVEC with Hcy resulted in a two-fold increase in LSP-mediated induction of leukocyte adhesion. The latter effect was significantly inhibited by anti-VCAM-1 antibodies. Together, these findings suggest that Hcy sensitizes HUVEC to the effect of inflammatory mediators thrombin and LPS, at least in part through VCAM-1 expression and function. PMID:18406566

  8. Establishment of the model of vascular endothelial cell membrane chromatography and its preliminary application

    Institute of Scientific and Technical Information of China (English)

    LI YiPing; HE LangChong

    2007-01-01

    A model of vascular endothelial cell membrane chromatography was established by using an ECV304 cell membrane stationary phase (ECV304 CMSP) prepared by immobilizing the ECV304 cell membrane onto the surface of silica carrier. The surface and chromatographic characteristics of ECV304 CMSP were studied. The active component from Caulophyllum robustum was screened by using the model of vascular endothelial cell membrane chromatography. The interaction between the active component and membrane receptor was determined by using a replace experiments. The effect of the active component was tested by using tube formation of ECV304 cell. The results indicated that the model of ECV304 cell membrane chromatograph (ECV304 CMC) can stimulate the interaction between drug and receptor in vitro and the retention characteristics of taspine as active component was similar to that of model molecule in the model of ECV304 CMC. And therefore, taspine acted on VEGFR2 and inhibited the tube formation of ECV304 cell induced by VEGF. This model can be used to screen definite active component as a screening model.

  9. Association of Chemerin and Vascular Endothelial Growth Factor (VEGF) with Diabetic Nephropathy

    Science.gov (United States)

    Lin, Shuhua; Teng, Jian; Li, Jixia; Sun, Fang; Yuan, Dong; Chang, Jing

    2016-01-01

    Background Diabetic nephropathy (DN) is a common complication of diabetes, caused by diabetic microvascular lesions. The pathogenesis of DN is complicated, involving genetics, physics, chemistry, and environmental factors. Chemerin is a fat cell factor that participates in regulating inflammation. Vascular endothelial growth factor (VEGF) promotes vascular endothelial cell proliferation, differentiation, and angiogenesis. The relationship role of Chemerin and VEGF in DN is not fully understood. Material/Methods SD rats were randomly divided into 2 groups: the control group and the DN group. Streptozotocin was used to construct the DN model. Serum creatinine (Scr), blood urea nitrogen (BUN), and urine microalbumin (UAlb) were detected. Real-time PCR and Western blot were used to test Chemerin and VEGF mRNA and protein expression in kidney tissue. ELISA was performed to test TGF-β1, TNF-α, and INF-γ levels. The correlation of Chemerin and VEGF with renal function and inflammatory factors was analyzed. Results DN group rats showed obviously increased Scr and BUN levels, and elevated TGF-β1, TNF-α, and INF-γ secretion (P<0.05). Compared with controls, Chemerin and VEGF were clearly overexpressed in the DN group (P<0.05). Chemerin and VEGF expression were positively correlated with inflammatory factors and renal function. Conclusions Chemerin and VEGF play important roles in DN by regulating inflammatory factors and renal function. They may be treated as indicators of DN. PMID:27612613

  10. Physical exercise and vascular endothelial growth factor (VEGF) in elderly: A systematic review.

    Science.gov (United States)

    Vital, Thays Martins; Stein, Angelica Miki; de Melo Coelho, Flávia Gomes; Arantes, Franciel José; Teodorov, Elizabeth; Santos-Galduróz, Ruth Ferreira

    2014-01-01

    The aim of this study was to conduct a systematic review of studies that verified the effects of physical exercise on vascular endothelial growth factor (VEGF) in elderly. The bibliographic search was conducted in five database, from 1990 to 2013, with the following keywords and boolean operators: physical exercise OR physical exercise OR physical therapy OR exercise OR training AND VEGF OR vascular endothelial growth factor AND aged OR older OR elderly. The inclusion criteria were: (1) sample including elderly with average age of 60; (2) studies that verified the effects of acute exercise; (3) studies that verified the effects of chronic physical exercise; (4) studies with humans; (5) randomized controlled trials, randomized non-controlled trials, non-randomized controlled trials, non-randomized and non-controlled trials; (6) assessment of VEGF peripheral concentrations. Ten studies were selected, and that four of them verified an increase of VEGF concentrations after practicing physical exercise and six studies did not verify any change on VEGF concentrations. Different populations found in this study and the different exercise protocols applied in the studies of this review make it difficult to establish parameters of what would be the best type of exercise to promote an increase on the concentrations of VEGF in the elderly. Therefore, we suggest that further studies can be performed, so that we can establish some recommendations for this population. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  11. Degradable poly(apigenin) polymer inhibits tumor cell adhesion to vascular endothelial cells.

    Science.gov (United States)

    Cochran, David B; Gray, Lindsay N; Anderson, Kimberly W; Dziubla, Thomas D

    2016-10-01

    Cancer and the inflammatory system share a complex intertwined relationship. For instance, in response to an injury or stress, vascular endothelial cells will express cell adhesion molecules as a means of recruiting leukocytes. However, circulating tumor cells (CTCs) have been shown to highjack this expression for the adhesion and invasion during the metastatic cascade. As such, the initiation of endothelial cell inflammation, either by surgical procedures (cancer resection) or chemotherapy can inadvertently increase the metastatic potential of CTCs. Yet, systemic delivery of anti-inflammatories, which weaken the entire immune system, may not be preferred in some treatment settings. In this work, we demonstrate that a long-term releasing flavone-based polymer and subsequent nanoparticle delivery system can inhibit tumor cell adhesion, through the suppression of endothelial cell adhesion molecule expression. The degradation of a this anti-inflammatory polymer provides longer term, localized release profile of active therapeutic drug in nanoparticle form as compared with that of the free drug, permitting more targeted anti-metastatic therapies. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1438-1447, 2016.

  12. Transdifferentiation of endothelial cells to smooth muscle cells play an important role in vascular remodelling

    Science.gov (United States)

    Coll-Bonfill, Núria; Musri, Melina Mara; Ivo, Victor; Barberà, Joan Albert; Tura-Ceide, Olga

    2015-01-01

    Pulmonary artery remodelling it is a major feature of pulmonary hypertension (PH). It is characterised by cellular and structural changes of the pulmonary arteries causing higher pulmonar vascular resistance and right ventricular failure. Abnormal deposition of smooth muscle-like (SM-like) cells in normally non-muscular, small diameter vessels and a deregulated control of endothelial cells are considered pathological features of PH. The origin of the SM-like cells and the mechanisms underlying the development and progression of this remodelling process are not understood. Endothelial cells within the intima may migrate from their organised layer of cells and transition to mesenchymal or SM-like phenotype in a process called endothelial-mesenchymal transition (EnMT). Traditionally, Waddington’s epigenetic landscape illustrates that fates of somatic cells are progressively determined to compulsorily follow a downhill differentiation pathway. EnMT induces the transformation of cells with stem cell traits, therefore contrasting Waddington’s theory and confirming that cell fate seems to be far more flexible than previously thought. The prospect of therapeutic inhibition of EnMT to delay or prevent PH may represent a promising new treatment modality. PMID:25973327

  13. Transdifferentiation of endothelial cells to smooth muscle cells play an important role in vascular remodelling.

    Science.gov (United States)

    Coll-Bonfill, Núria; Musri, Melina Mara; Ivo, Victor; Barberà, Joan Albert; Tura-Ceide, Olga

    2015-01-01

    Pulmonary artery remodelling it is a major feature of pulmonary hypertension (PH). It is characterised by cellular and structural changes of the pulmonary arteries causing higher pulmonar vascular resistance and right ventricular failure. Abnormal deposition of smooth muscle-like (SM-like) cells in normally non-muscular, small diameter vessels and a deregulated control of endothelial cells are considered pathological features of PH. The origin of the SM-like cells and the mechanisms underlying the development and progression of this remodelling process are not understood. Endothelial cells within the intima may migrate from their organised layer of cells and transition to mesenchymal or SM-like phenotype in a process called endothelial-mesenchymal transition (EnMT). Traditionally, Waddington's epigenetic landscape illustrates that fates of somatic cells are progressively determined to compulsorily follow a downhill differentiation pathway. EnMT induces the transformation of cells with stem cell traits, therefore contrasting Waddington's theory and confirming that cell fate seems to be far more flexible than previously thought. The prospect of therapeutic inhibition of EnMT to delay or prevent PH may represent a promising new treatment modality.

  14. Substrate specificity of the agonist-stimulated release of polyunsaturated fatty acids from vascular endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Rosenthal, M.D.; Garcia, M.C.; Sprecher, H. (Eastern Virginia Medical School, Norfolk (USA))

    1989-11-01

    Stimulation of vascular endothelial cells with agonists such as histamine and thrombin results in release of arachidonic acid from membrane lipids and subsequent eicosanoid synthesis. As shown previously, the agonist-stimulated deacylation is specific for arachidonate, eicosapentaenoate, and 5,8,11-eicosatrienoate. This study has utilized radiolabeled fatty acids differing in chain length and position of double bonds to further elucidate the fatty acyl specificity of agonist-stimulated deacylation. Replicate wells of confluent human umbilical vein endothelial cells were incubated with 14C-labeled fatty acids and then challenged with histamine, thrombin, or the calcium ionophore A23187. Comparison of the results obtained with isomeric eicosatetraenoic fatty acids with initial double bonds at carbons 4, 5, or 6 indicated that the deacylation induced by all three agonists exhibited marked specificity for the cis-5 double bond. Lack of stringent chain length specificity was indicated by agonist-stimulated release of 5,8,11,14- tetraenoic fatty acids with 18, 19, 20, and 21 carbons. Release of 5,8,14-(14C)eicosatrienoate was two-to threefold that of 5,11,14-(14C)eicosatrienoate, thus indicating that the cis-8 double bond may also contribute to the stringent recognition by the agonist-sensitive phospholipase. The present study has also demonstrated that histamine, thrombin, and A23187 do not stimulate release of docosahexaenoate from endothelial cells.

  15. Magnetic ferroferric oxide nanoparticles induce vascular endothelial cell dysfunction and inflammation by disturbing autophagy.

    Science.gov (United States)

    Zhang, Lu; Wang, XueQin; Miao, YiMing; Chen, ZhiQiang; Qiang, PengFei; Cui, LiuQing; Jing, Hongjuan; Guo, YuQi

    2016-03-01

    Despite the considerable use of magnetic ferroferric oxide nanoparticles (Fe3O4NPs) worldwide, their safety is still an important topic of debate. In the present study, we detected the toxicity and biological behavior of bare-Fe3O4NPs (B-Fe3O4NPs) on human umbilical vascular endothelial cells (HUVECs). Our results showed that B-Fe3O4NPs did not induce cell death within 24h even at concentrations up to 400 μg/ml. The level of nitric oxide (NO) and the activity of endothelial NO synthase (eNOS) were decreased after exposure to B-Fe3O4NPs, whereas the levels of proinflammatory cytokines were elevated. Importantly, B-Fe3O4NPs increased the accumulation of autophagosomes and LC3-II in HUVECs through both autophagy induction and the blockade of autophagy flux. The levels of Beclin 1 and VPS34, but not phosphorylated mTOR, were increased in the B-Fe3O4NP-treated HUVECs. Suppression of autophagy induction or stimulation of autophagy flux, at least partially, attenuated the B-Fe3O4NP-induced HUVEC dysfunction. Additionally, enhanced autophagic activity might be linked to the B-Fe3O4NP-induced production of proinflammatory cytokines. Taken together, these results demonstrated that B-Fe3O4NPs disturb the process of autophagy in HUVECs, and eventually lead to endothelial dysfunction and inflammation.

  16. N-Acetylcysteine, a glutathione precursor, reverts vascular dysfunction and endothelial epigenetic programming in intrauterine growth restricted guinea pigs.

    Science.gov (United States)

    Herrera, Emilio A; Cifuentes-Zúñiga, Francisca; Figueroa, Esteban; Villanueva, Cristian; Hernández, Cherie; Alegría, René; Arroyo-Jousse, Viviana; Peñaloza, Estefania; Farías, Marcelo; Uauy, Ricardo; Casanello, Paola; Krause, Bernardo J

    2017-02-15

    Intrauterine growth restriction (IUGR) is associated with vascular dysfunction, oxidative stress and signs of endothelial epigenetic programming of the umbilical vessels. There is no evidence that this epigenetic programming is occurring on systemic fetal arteries. In IUGR guinea pigs we studied the functional and epigenetic programming of endothelial nitric oxide synthase (eNOS) (Nos3 gene) in umbilical and systemic fetal arteries, addressing the role of oxidative stress in this process by maternal treatment with N-acetylcysteine (NAC) during the second half of gestation. The present study suggests that IUGR endothelial cells have common molecular markers of programming in umbilical and systemic arteries. Notably, maternal treatment with NAC restores fetal growth by increasing placental efficiency and reverting the functional and epigenetic programming of eNOS in arterial endothelium in IUGR guinea pigs. In humans, intrauterine growth restriction (IUGR) is associated with vascular dysfunction, oxidative stress and signs of endothelial programming in umbilical vessels. We aimed to determine the effects of maternal antioxidant treatment with N-acetylcysteine (NAC) on fetal endothelial function and endothelial nitric oxide synthase (eNOS) programming in IUGR guinea pigs. IUGR was induced by implanting ameroid constrictors on uterine arteries of pregnant guinea pigs at mid gestation, half of the sows receiving NAC in the drinking water (from day 34 until term). Fetal biometry and placental vascular resistance were followed by ultrasound throughout gestation. At term, umbilical arteries and fetal aortae were isolated to assess endothelial function by wire-myography. Primary cultures of endothelial cells (ECs) from fetal aorta, femoral and umbilical arteries were used to determine eNOS mRNA levels by quantitative PCR and analyse DNA methylation in the Nos3 promoter by pyrosequencing. Doppler ultrasound measurements showed that NAC reduced placental vascular resistance

  17. Effect of adjuvant argatroban therapy on neurological function, endothelial injury and inflammation state in patient with acute cerebral infarction

    Institute of Scientific and Technical Information of China (English)

    Nan Che

    2016-01-01

    Objective:To analyze the effect of adjuvant argatroban therapy on neurological function, endothelial injury and inflammation state in patient with acute cerebral infarction.Methods:A total of 118 patients with acute cerebral infarction were divided into observation group and control group according to the random number table, control group received conventional treatment, observation group received argatroban + conventional treatment, and then differences in TCD cerebral blood flow, serum neurological function, endothelial injury and inflammatory marker levels were compared between two groups after treatment.Results:TCD MCA and ACA values of observation group after treatment were higher than those of control group (P<0.05); serum neurological function indexes copeptin, NT-proBNP, PAO and S-100B levels of observation group after treatment were lower than those of control group, endothelial injury index ET-1 level was lower than that of control group, NO and CGRP levels were higher than those of control group, and inflammatory markers hs-CRP, TNF-α, IL-6, MMP-9 and Lp-PLA2 levels were lower than those of control group (P<0.05).Conclusions:Adjuvant argatroban therapy can optimize the overall condition in patients with acute cerebral infarction, and plays a positive role in improving the neurological function, reducing endothelial injury and inflammation state, etc.

  18. Inhibition of the proliferation and acceleration of migration of vascular endothelial cells by increased cysteine-rich motor neuron 1

    Energy Technology Data Exchange (ETDEWEB)

    Nakashima, Yukiko; Morimoto, Mayuka [Department of Immunobiology, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women' s University, 11-68 Koshien Kyuban-cho, Nishinomiya, Hyogo 663-8179 (Japan); Toda, Ken-ichi [Department of Dermatology, Kitano Hospital, The Tazuke Kofukai Nedical Institute, 2-4-20 Ohgimachi, Kita-ku, Osaka 530-8480 (Japan); Shinya, Tomohiro; Sato, Keizo [Department of Clinical Biochemistry, School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, Nobeoka, Miyazaki 882-8508 (Japan); Takahashi, Satoru, E-mail: imwalrus@mukogawa-u.ac.jp [Department of Immunobiology, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women' s University, 11-68 Koshien Kyuban-cho, Nishinomiya, Hyogo 663-8179 (Japan); Institute for Biosciences, Mukogawa Women' s University, 11-68 Koshien Kyuban-cho, Nishinomiya, Hyogo 663-8179 (Japan)

    2015-07-03

    Cysteine-rich motor neuron 1 (CRIM1) is upregulated only in extracellular matrix gels by angiogenic factors such as vascular endothelial growth factor (VEGF). It then plays a critical role in the tube formation of endothelial cells. In the present study, we investigated the effects of increased CRIM1 on other endothelial functions such as proliferation and migration. Knock down of CRIM1 had no effect on VEGF-induced proliferation or migration of human umbilical vein endothelial cells (HUVECs), indicating that basal CRIM1 is not involved in the proliferation or migration of endothelial cells. Stable CRIM1-overexpressing endothelial F-2 cells, termed CR1 and CR2, were constructed, because it was difficult to prepare monolayer HUVECs that expressed high levels of CRIM1. Proliferation was reduced and migration was accelerated in both CR1 and CR2 cells, compared with normal F-2 cells. Furthermore, the transient overexpression of CRIM1 resulted in decreased proliferation and increased migration of bovine aortic endothelial cells. In contrast, neither proliferation nor migration of COS-7 cells were changed by the overexpression of CRIM1. These results demonstrate that increased CRIM1 reduces the proliferation and accelerates the migration of endothelial cells. These CRIM1 effects might contribute to tube formation of endothelial cells. CRIM1 induced by angiogenic factors may serve as a regulator in endothelial cells to switch from proliferating cells to morphological differentiation. - Highlights: • CRIM1 was upregulated only in tubular endothelial cells, but not in monolayers. • Increased CRIM1 reduced the proliferation of endothelial cells. • Increased CRIM1 accelerated the migration of endothelial cells. • Increased CRIM1 had no effect on the proliferation or migration of COS-7 cells.

  19. ILK mediates LPS-induced vascular adhesion receptor expression and subsequent leucocyte trans-endothelial migration.

    Science.gov (United States)

    Hortelano, Sonsoles; López-Fontal, Raquel; Través, Paqui G; Villa, Natividad; Grashoff, Carsten; Boscá, Lisardo; Luque, Alfonso

    2010-05-01

    The inflammatory response to injurious agents is tightly regulated to avoid adverse consequences of inappropriate leucocyte accumulation or failed resolution. Lipopolysaccharide (LPS)-activated endothelium recruits leucocytes to the inflamed tissue through controlled expression of membrane-associated adhesion molecules. LPS responses in macrophages are known to be regulated by integrin-linked kinase (ILK); in this study, we investigated the role of ILK in the regulation of the LPS-elicited inflammatory response in endothelium. This study was performed on immortalized mouse endothelial cells (EC) isolated from lung and coronary vasculature. Cells were thoroughly characterized and the role of ILK in the regulation of the LPS response was investigated by suppressing ILK expression using siRNA and shRNA technologies. Phenotypic and functional analyses confirmed that the immortalized cells behaved as true EC. LPS induced the expression of the inflammatory genes E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). ILK knockdown impaired LPS-mediated endothelial activation by preventing the induction of ICAM-1 and VCAM-1. Blockade of the LPS-induced response inhibited the inflammatory-related processes of firm adhesion and trans-endothelial migration of leucocytes. ILK is involved in the expression of cell adhesion molecules by EC activated with the inflammatory stimulus LPS. This reduced expression modulates leucocyte adhesion to the endothelium and the extravasation process. This finding suggests ILK as a potential anti-inflammatory target for the development of vascular-specific treatments for inflammation-related diseases.

  20. Inhibitive effects of anti-oxidative vitamins on mannitol-induced apoptosis of vascular endothelial cells

    Institute of Scientific and Technical Information of China (English)

    PAN Kai-yu; SHEN Mei-ping; YE Zhi-hong; DAI Xiao-na; SHANG Shi-qiang

    2006-01-01

    Objective: Study blood vessel injury and gene expression indicating vascular endothelial cell apoptosis induced by mannitol with and without administration of anti-oxidative vitamins. Methods: Healthy rabbits were randomly divided into four groups. Mannitol was injected into the vein of the rabbit ear in each animal. Pre-treatment prior to mannitol injection was performed with normal saline (group B), vitamin C (group C) and vitamin E (group D). Blood vessel injury was assessed under electron and light microscopy. In a second experiment, cell culture specimen of human umbilical vein endothelial cells were treated with mannitol. Pre-treatment was done with normal saline (sample B), vitamin C (sample C) and vitamin E (sample D).Total RNA was extracted with the original single step procedure, followed by hybridisation and analysis of gene expression.Results: In the animal experiment, serious blood vessel injury was seen in group A and group B. Group D showed light injury only,and normal tissue without pathological changes was seen in group C. Of all 330 apoptosis-related genes analysed in human cell culture specimen, no significant difference was seen after pre-treatment with normal saline, compared with the gene chip without pre-treatment. On the gene chip pre-treated with vitamin C, 45 apoptosis genes were down-regulated and 34 anti-apoptosis genes were up-regulated. Pre-treatment with vitamin E resulted in the down-regulation of 3 apoptosis genes. Conclusion: Vitamin C can protect vascular endothelial cells from mannitol-induced injury.

  1. Vascular endothelial growth factor inhibitors: investigational therapies for the treatment of psoriasis

    Directory of Open Access Journals (Sweden)

    Weidemann AK

    2013-09-01

    Full Text Available Anja K Weidemann,1 Ania A Crawshaw,2 Emily Byrne,3 Helen S Young1 1The Dermatology Centre, Salford Royal NHS Foundation Trust, The University of Manchester, Manchester, UK; 2Royal Sussex County Hospital, Brighton, UK; 3University Hospital of South Manchester, Manchester, UK Abstract: Psoriasis is a common inflammatory autoimmune condition in which environmental factors and genetic predisposition contribute to the development of disease in susceptible individuals. Angiogenesis is known to be a key pathogenic feature of psoriasis. Local and systemic elevation of vascular endothelial growth factor (VEGF-A has been demonstrated in the skin and plasma of patients with psoriasis and is known to correlate with improvement following some traditional psoriasis treatments. A number of VEGF inhibitors are licensed for the treatment of malignancies and eye disease and isolated case reports suggest that some individuals with psoriasis may improve when exposed to these agents. The small number of cases and lack of unified reporting measures makes it difficult to draw generalizations and underline the heterogeneity of psoriasis as a disease entity. Though not yet licensed for the treatment of psoriasis in humans, experimental data supports the potential of VEGF inhibitors to influence relevant aspects of human cell biology (such as endothelial cell differentiation and to improve animal models of skin disease. Given the multi-factorial nature of psoriasis it is unlikely that VEGF inhibitors will be effective in all patients, however they have the potential to be a valuable addition to the therapeutic arsenal in selected cases. Current VEGF inhibitors in clinical use are associated with a number of potentially serious side effects including hypertension, left ventricular dysfunction, and gastrointestinal perforation. Such risks require careful consideration in psoriasis populations particularly in light of growing concerns linking psoriasis to increased

  2. Primeiro consenso brasileiro do tratamento da fase aguda do acidente vascular cerebral

    Directory of Open Access Journals (Sweden)

    2001-01-01

    Full Text Available Este texto apresenta a síntese das conclusões do Iº Consenso Brasileiro do Tratamento da Fase Aguda do Acidente Vascular Cerebral (AVC. Tratou-se de reunião patrocinada e coordenada pela Sociedade Brasileira de Doenças Cerebrovasculares, com neurologistas especializados nas doenças cerebrovasculares, que analisaram os principais itens da conduta dos AVC.

  3. Study on the Relationship between Plasma Homocysteine and Acute Cerebral Vascular Disease

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    The levels of plasma homocysteine were determined by using high-performance liquid chromatographic method. It was found that plasma homocysteine levels were significantly higher in the patients with stroke than that in the controls. There was no correlation between plasma homocysteine levels and hypertension, smoking, concentrations of blood glucose or hypertriglyceridesemia. It was suggested that hyperhomocysteinemia may be an independent risk factor for acute cerebral vascular disease.

  4. Vascular endothelial and smooth muscle cell culture on NaOH-treated poly(epsilon-caprolactone) films: a preliminary study for vascular graft development.

    Science.gov (United States)

    Serrano, María Concepción; Portolés, María Teresa; Vallet-Regí, María; Izquierdo, Isabel; Galletti, Lorenzo; Comas, Juan Valentín; Pagani, Raffaella

    2005-05-23

    Tissue engineering offers the potential of providing vessels that can be used to replace diseased and damaged native blood vessels. The endothelization of a synthetic vascular graft minimizes the failures associated with blood clotting and platelet activation. The aim of this study was to culture vascular-derived endothelial and smooth muscle cells on both untreated and NaOH-treated poly(epsilon-caprolactone) (PCL) films, a biocompatible and bio-resorbable polymer, and to evaluate the behavior of both cell types as a preliminary study for vascular graft development. PCL films were prepared by hot pressing; characterized by DSC, IR, SEM, and scanning force microscopy; and treated with NaOH to increase the surface hydrophilicity before cell culture. Endothelial and smooth muscle cells, isolated from pig cava vein, were characterized by immunofluorescence and confocal microscopy studies of endothelial nitric oxide synthase and alpha-smooth muscle actin. Good adhesion, growth, viability and morphology of both the endothelial and smooth muscle cells on PCL films were obtained, but a light stimulation of mitochondrial activity was observed during short culture times. NaOH treatment improved the adhesion and enhanced the proliferation in both cell types. This verified the possible use of this modified polymer as a support in the preparation of a synthetic vascular graft. [Diagram: see text] SEM micrograph of smooth muscle cells cultured on NaOH-treated PCL film. (Original magnification: 1000x).

  5. Role of endovascular embolization for trigeminal neuralgia related to cerebral vascular malformation.

    Science.gov (United States)

    Ge, Huijian; Lv, Xianli; Jin, Hengwei; He, Hongwei; Li, Youxiang

    2016-10-01

    The objective of this article is to describe the trigeminal neuralgia related to cerebral vascular malformation that is rarely reported and the experience referring to endovascular treatment. A total of 10 patients who had cerebral vascular malformation (AVM and dAVF) in a single center presented with trigeminal neuralgia. Clinical and angiographic presentations as well as their clinical outcomes after embolization were reviewed. Of the 10 cases, seven dAVFs and three AVMs were detected. In contrast to the dilated feeding arteries, an ectasia of the draining vein that is adjacent to the root entry zone of the trigeminal nerve such as the petrosal vein and lateral mesencephalic vein has the major role in causing the trigeminal neuralgia. All of these patients had relief of facial pain after endovascular embolization during follow-up (mean 57.3 months, range 5 to 100 months). There were no permanent neurological deficits. Endovascular embolization is an effective method in treating trigeminal neuralgia related to cerebral vascular malformation. © The Author(s) 2016.

  6. Long bone structure and strength depend on BMP2 from osteoblasts and osteocytes, but not vascular endothelial cells.

    Directory of Open Access Journals (Sweden)

    Sarah H McBride

    Full Text Available The importance of bone morphogenetic protein 2 (BMP2 in the skeleton is well known. BMP2 is expressed in a variety of tissues during development, growth and healing. In this study we sought to better identify the role of tissue-specific BMP2 during post-natal growth and to determine if BMP2 knockout affects the ability of terminally differentiated cells to create high quality bone material. We targeted BMP2 knockout to two differentiated cell types known to express BMP2 during growth and healing, early-stage osteoblasts and their progeny (osterix promoted Cre and vascular endothelial cells (vascular-endothelial-cadherin promoted Cre. Our objectives were to assess post-natal bone growth, structure and strength. We hypothesized that removal of BMP2 from osteogenic and vascular cells (separately would result in smaller skeletons with inferior bone material properties. At 12 and 24 weeks of age the osteoblast knockout of BMP2 reduced body weight by 20%, but the vascular knockout had no effect. Analysis of bone in the tibia revealed reductions in cortical and cancellous bone size and volume in the osteoblast knockout, but not in the vascular endothelial knockout. Furthermore, forelimb strength testing revealed a 30% reduction in ultimate force at both 12 and 24 weeks in the osteoblast knockout of BMP2, but no change in the vascular endothelial knockout. Moreover, mechanical strength testing of femurs from osteoblast knockout mice demonstrated an increased Young's modulus (greater than 35% but decreased post-yield displacement (greater than 50% at both 12 and 24 weeks of age. In summary, the osteoblast knockout of BMP2 reduced bone size and altered mechanical properties at the whole-bone and material levels. Osteoblast-derived BMP2 has an important role in post-natal skeletal growth, structure and strength, while vascular endothelial-derived BMP2 does not.

  7. Long bone structure and strength depend on BMP2 from osteoblasts and osteocytes, but not vascular endothelial cells.

    Science.gov (United States)

    McBride, Sarah H; McKenzie, Jennifer A; Bedrick, Bronwyn S; Kuhlmann, Paige; Pasteris, Jill D; Rosen, Vicki; Silva, Matthew J

    2014-01-01

    The importance of bone morphogenetic protein 2 (BMP2) in the skeleton is well known. BMP2 is expressed in a variety of tissues during development, growth and healing. In this study we sought to better identify the role of tissue-specific BMP2 during post-natal growth and to determine if BMP2 knockout affects the ability of terminally differentiated cells to create high quality bone material. We targeted BMP2 knockout to two differentiated cell types known to express BMP2 during growth and healing, early-stage osteoblasts and their progeny (osterix promoted Cre) and vascular endothelial cells (vascular-endothelial-cadherin promoted Cre). Our objectives were to assess post-natal bone growth, structure and strength. We hypothesized that removal of BMP2 from osteogenic and vascular cells (separately) would result in smaller skeletons with inferior bone material properties. At 12 and 24 weeks of age the osteoblast knockout of BMP2 reduced body weight by 20%, but the vascular knockout had no effect. Analysis of bone in the tibia revealed reductions in cortical and cancellous bone size and volume in the osteoblast knockout, but not in the vascular endothelial knockout. Furthermore, forelimb strength testing revealed a 30% reduction in ultimate force at both 12 and 24 weeks in the osteoblast knockout of BMP2, but no change in the vascular endothelial knockout. Moreover, mechanical strength testing of femurs from osteoblast knockout mice demonstrated an increased Young's modulus (greater than 35%) but decreased post-yield displacement (greater than 50%) at both 12 and 24 weeks of age. In summary, the osteoblast knockout of BMP2 reduced bone size and altered mechanical properties at the whole-bone and material levels. Osteoblast-derived BMP2 has an important role in post-natal skeletal growth, structure and strength, while vascular endothelial-derived BMP2 does not.

  8. Autonomic cerebral vascular response to sildenafil in diabetic patient

    Directory of Open Access Journals (Sweden)

    Al-Amran Fadhil G

    2012-01-01

    Full Text Available Abstract Background Erectile dysfunction is a common problem in type 2 diabetic patients who are at higher risk of cerebrovascular events, and it's recorded with sildenafil, a drug which is primarily used for erectile dysfunction. Objectives We tested the hypothesis whether or not sildenafil modulates cerebrovascular reactivity (CVR in patients with type 2 diabetes mellitus. Methods A total of 35 male participants were enrolled; eighteen with type 2 diabetes mellitus matched with seventeen normal individuals. Transcranial Doppler Ultrasonographic examination (TCD was performed for all participants to insonate the middle cerebral artery (MCA through a trans-temporal window. CVR was assessed by using breath holding (BH-hyperventilation (HV test, before and after oral 50 mg sildenafil; recordings were analyzed by using SPSS program version 12. Results In normal individuals, sildenafil did not result in statistically significant change in breath holding index (BHI from 0.91 ± 0.11 to 0.81 ± 0.09 and full range of vasodilatation (FVD from (59.4% ± 6.3% to (53.7% ± 4.9%. In diabetic patients, giving sildenafil resulted in significant increase in BHI (from 0.74 ± 0.14 to 1.03 ± 0.14 and FVD (from 60.2% ± 4.96% to 74% ± 4.8%, (p Conclusion Sildenafil significantly improves CVR in type 2 diabetic patients but not in normal subjects.

  9. Expression of GLI1 correlates with expression of lymphangiogenesis proteins, vascular endothelial growth factor C and vascular endothelial growth factor receptor 3, in colorectal cancer.

    Science.gov (United States)

    Hong, Kwang Dae; Lee, Youngseok; Kim, Baek-Hui; Lee, Sun Il; Moon, Hong Young

    2013-02-01

    Aberrant activation of the hedgehog (Hh) signaling pathway is associated with tumorigenesis in various tissues. In colorectal cancer (CRC), evidence for Hh activation is inconsistent, and the relationship between the Hh signaling pathway and lymphangiogenesis has not been studied. The aim of this study was to determine the relationship between Hh signaling and lymphangiogenesis and the association of this relationship with lymph node metastasis in CRC. We investigated 189 patients who underwent curative surgical resection for CRC between 2002 and 2004 at Korea University Guro Hospital. Paraffin-embedded specimens of colorectal adenocarcinoma and adjacent normal mucosa were evaluated. Immunohistochemical staining for Sonic hedgehog (Shh), Gli1, vascular endothelial growth factor C (VEGFC), and VEGF receptor 3 (VEGFR3) was performed for each specimen. Tumor specimen showed significantly strong staining of Shh, Gli1, VEGFC, and VEGFR3 compared with a normal specimen. Shh expression was not associated with Gli1 expression. Gli1 expression correlated positively with VEGFC and VEGFR3 expression (P < 0.05 in both) but not with lymph node metastasis. Activation of the Hh signaling pathway associated with Gli1 promotes expression of lymphangiogenesis proteins, VEGFC and VEGFR3, in CRC. Further studies are necessary to determine the association of this relationship with lymph node metastasis in CRC.

  10. Overexpression of Vascular Endothelial Growth Factor in Restenotic Abdominal Aorta of Rabbits

    Institute of Scientific and Technical Information of China (English)

    尹瑞兴; 杨德寨; 吴海; 黄凯; 巫相宏; 陈宇明

    2002-01-01

    Objective To investigatethe expression of vascular endothelial growth factor (VEGF) in the wall of normal and restenotic abdominal aorta of rabbits. Methods Restenotic model was developed by balloon-injured abdominal aorta in eight male New Zealand White rabbits fed with a 2.0% cholesterol diet beginning two weeks before operation and continuing four weeks after procedure. At the end of 4 weeks after injury, the animals underwent total body perfusion fixation. Then, the abdominal aorta from iliac artery root to the diaphragm was harvested and post-fixed in 10 % neutral formalin for 16hours. Eight male animals fed with general diet were used for a normal control. The VEGF protein level in normal and restenotic abdominal aorta of rabbits was studied by means of immunohistochemistry. Results VEGF protein was detected in 5 (62.5 % ) of 8normal abdominal aorta, 3 showed faint staining, and the remaining 2 showed moderate VEGF expression.VEGF expression at the protein level was identified in all 8 restenotic specimens, 2 showed faint staining, 4showed moderate staining, and the remaining 2showed strong VEGF expression. In contrast to normal vessels, VEGF in restenotic specimens was distinctly expressed at sites that contained clustered macrophages and proliferating smooth muscle cells as well as endothelial cells. VEGF immunostaining was more extensive in restenotic specimens (2. 00 ± 0.76)than in normal vessels (0.82 ±0. 83, P < 0.01) .Microvessels were found in 7 of the 8 restenotic lesions, but only one lesion showed VEGF staining in endothelial cells of the microvessels. Conclusion VEGF expression is consistently more intense in sections of restenotic abdominal aorta than in those of normal abdominal aorta. The VEGF expressed by the smooth muscle cells and foamy macrophages in the restenotic arteries may act as a local and endogenous regulator of endothelial cell functions, including maintenance and repair of luminal endothelium, and formation of intimal

  11. Possible vasculoprotective role of linagliptin against sodium arsenite-induced vascular endothelial dysfunction.

    Science.gov (United States)

    Jyoti, Uma; Kansal, Sunil Kumar; Kumar, Puneet; Goyal, Sandeep

    2016-02-01

    Vascular endothelial dysfunction (VED) interrupts the integrity and function of endothelial lining through enhanced markers of oxidative stress and decrease endothelial nitric oxide synthase (eNOS) expression. The main aim of the present study has been designed to investigate the possible vasculoprotective role of linagliptin against sodium arsenite-induced VED. Sodium arsenite (1.5 mg/kg, i.p., 2 weeks) abrogated the acetylcholine-induced, endothelium-dependent vasorelaxation by depicting the decrease in serum nitrite/nitrate concentration, reduced glutathione level, and simultaneously enhance the thiobarbituric acid reactive substances (TBARS) level, superoxide level, and tumor necrosis factor-alpha. These elevated markers interrupt the integrity of endothelial lining of thoracic aorta which was assessed histologically. The study elicits dose dependent effect of linagliptin (1.5 mg/kg, i.p. and 3 mg/kg, i.p.) or atorvastatin (30 mg/kg, p.o.) treatment, improved the endothelium-dependent independent relaxation, improve the integrity of endothelium lining which was assessed histologically by enhancing the serum nitrite/nitrate level, reduced glutathione level and simultaneously decreasing the TBARS level, superoxide anion level and tumor necrosis factor-alpha (TNF-α) level. L-NAME (25 mg/kg, i.p.), eNOS inhibitor, abrogated the ameliorative potential of linagliptin. However, the ameliorative potential of linagliptin has been enhanced by l-arginine (200 mg/kg, i.p.) which elicits that ameliorative potential of linagliptin was through eNOS signaling cascade and it may be concluded that linagliptin 3 mg/kg, i.p. has more significantly activated the eNOS and decreased the oxidative markers than linagliptin 1.5 mg/kg, i.p. and prevented sodium arsenite-induced VED.

  12. Gomisin J from Schisandra chinensis induces vascular relaxation via activation of endothelial nitric oxide synthase.

    Science.gov (United States)

    Park, Ji Young; Choi, Young Whan; Yun, Jung Wook; Bae, Jin Ung; Seo, Kyo Won; Lee, Seung Jin; Park, So Youn; Kim, Chi Dae

    2012-01-01

    Gomisin J (GJ) is a lignan contained in Schisandra chinensis (SC) which is a well-known medicinal herb for improvement of cardiovascular symptoms in Korean. Thus, the present study examined the vascular effects of GJ, and also determined the mechanisms involved. Exposure of rat thoracic aorta to GJ (1-30μg/ml) resulted in a concentration-dependent vasorelaxation, which was more prominent in the endothelium (ED)-intact aorta. ED-dependent relaxation induced by GJ was markedly attenuated by pretreatment with L-NAME, a nitric oxide synthase (NOS) inhibitor. In the intact endothelial cells of rat thoracic aorta, GJ also enhanced nitric oxide (NO) production. In studies using human coronary artery endothelial cells, GJ enhanced phosphorylation of endothelial NOS (eNOS) at Ser(1177) with increased cytosolic translocation of eNOS, and subsequently increased NO production. These effects of GJ were attenuated not only by calcium chelators including EGTA and BAPTA-AM, but also by LY294002, a PI3K/Akt inhibitor, indicating calcium- and PI3K/Akt-dependent activation of eNOS by GJ. Moreover, the levels of intracellular calcium were increased immediately after GJ administration, but Akt phosphorylation was started to increase at 20min of GJ treatment. Based on these results with the facts that ED-dependent relaxation occurred rapidly after GJ treatment, it was suggested that the ED-dependent vasorelaxant effects of GJ were mediated mainly by calcium-dependent activation of eNOS with subsequent production of endothelial NO.

  13. Benfotiamine attenuates nicotine and uric acid-induced vascular endothelial dysfunction in the rat.

    Science.gov (United States)

    Balakumar, Pitchai; Sharma, Ramica; Singh, Manjeet

    2008-01-01

    The study has been designed to investigate the effect of benfotiamine, a thiamine derivative, in nicotine and uric acid-induced vascular endothelial dysfunction (VED) in rats. Nicotine (2 mg kg(-1)day(-1), i.p., 4 weeks) and uric acid (150 mg kg(-1)day(-1), i.p., 3 weeks) were administered to produce VED in rats. The development of VED was assessed by employing isolated aortic ring preparation and estimating serum and aortic concentration of nitrite/nitrate. Further, the integrity of vascular endothelium was assessed using the scanning electron microscopy (SEM) of thoracic aorta. Moreover, the oxidative stress was assessed by estimating serum thiobarbituric acid reactive substances (TBARS) and aortic superoxide anion generation. The administration of nicotine and uric acid produced VED by impairing the integrity of vascular endothelium and subsequently decreasing serum and aortic concentration of nitrite/nitrate and attenuating acetylcholine-induced endothelium dependent relaxation. Further, nicotine and uric acid produced oxidative stress, which was assessed in terms of increase in serum TBARS and aortic superoxide generation. However, treatment with benfotiamine (70 mg kg(-1)day(-1), p.o.) or atorvastatin (30 mg kg(-1)day(-1) p.o., a standard agent) markedly prevented nicotine and uric acid-induced VED and oxidative stress by improving the integrity of vascular endothelium, increasing the concentration of serum and aortic nitrite/nitrate, enhancing the acetylcholine-induced endothelium dependent relaxation and decreasing serum TBARS and aortic superoxide anion generation. Thus, it may be concluded that benfotiamine reduces the oxidative stress and consequently improves the integrity of vascular endothelium and enhances the generation of nitric oxide to prevent nicotine and uric acid-induced experimental VED.

  14. Vitamin D regulates the production of vascular endothelial growth factor: A triggering cause in the pathogenesis of rheumatic heart disease?

    Science.gov (United States)

    Sarkar, Subendu; Chopra, Seema; Rohit, Manoj Kumar; Banerjee, Dibyajyoti; Chakraborti, Anuradha

    2016-10-01

    Rheumatic heart disease (RHD) remains a major cause of cardiac related mortality and morbidity in the developing countries due to poor diagnosis and lack of proper therapeutics. The definite reason of heart valve injury during RHD is poorly understood. Valvular endothelial cells play an important role in pathogenesis of different cardiovascular diseases. Besides, the regulation of vitamin D (calciferol) and VEGF (vascular endothelial growth factor) results in the functional changes in endothelial cells. However, the crosstalk between vitamin D and VEGF in the pathogenesis of RHD is not yet unfurled. Evidences in the concerned fields are documented by searching through Google Scholar and Pubmed. Literature based survey has revealed that vascular endothelium, especially endothelial cells play important roles in valvular remodelling during cardiovascular diseases. Endothelial cell dysfunction leads to heart valve remodelling, which furthermore initiates the pathogenesis of valvular heart disease. Vitamin D has the potential to maintain the concentration of VEGF in the circulation and induce the function of endothelial cells. Hence, we hypothesize that vitamin D and VEGF homeostasis can alter the function of endothelial cells, which may subsequently trigger the valvular remodelling or even damage of heart valves during the progression of RHD pathogenesis. Our hypothesis shed light on the evidence based knowledge translation of plausible cellular phenomena due to vitamin D/VEGF homeostasis during valvular vandalism in RHD. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Involvement of vascular endothelial growth factor in nasal obstruction in patients with nasal allergy

    Directory of Open Access Journals (Sweden)

    Tetsuji Yamashita

    2000-01-01

    Full Text Available It has recently been shown that vascular endothelial growth factor (VEGF enhances vascular permeability and that mast cells produce VEGF, suggesting the involvement of VEGF in allergic diseases. In the present study we quantitatively analyzed VEGF in the nasal lavage fluid of patients with nasal allergy. We performed nasal antigen challenge with Japanese cedar pollen antigen in 10 healthy adult volunteers and in 10 cedar pollen IgE-positive patients with nasal allergy. In all patients with nasal allergy, VEGF and histamine levels in the nasal lavage fluid reached a peak 30 min after antigen challenge, then returned to prechallenge values 2 h after antigen challenge. In these patients, the histamine level increased three-fold, while the VEGF level increased 10-fold. However, in all healthy adult volunteers, VEGF and histamine levels did not increase. A stronger correlation was noted between the ratio of decreased nasal cavity volume and the ratio of increased VEGF levels (R = 0.823; P < 0.001 than between the ratio of nasal cavity volume and the ratio of increased histamine levels (R = 0.660; P < 0.01. These results suggest that VEGF may contribute to the pathogenesis of nasal obstruction in the early phase of nasal allergy as a new factor involved in increasing vascular permeability.

  16. Clarification of mural cell coverage of vascular endothelial cells by live imaging of zebrafish.

    Science.gov (United States)

    Ando, Koji; Fukuhara, Shigetomo; Izumi, Nanae; Nakajima, Hiroyuki; Fukui, Hajime; Kelsh, Robert N; Mochizuki, Naoki

    2016-04-15

    Mural cells (MCs) consisting of vascular smooth muscle cells and pericytes cover the endothelial cells (ECs) to regulate vascular stability and homeostasis. Here, we clarified the mechanism by which MCs develop and cover ECs by generating transgenic zebrafish lines that allow live imaging of MCs and by lineage tracing in vivo To cover cranial vessels, MCs derived from either neural crest cells or mesoderm emerged around the preformed EC tubes, proliferated and migrated along EC tubes. During their migration, the MCs moved forward by extending their processes along the inter-EC junctions, suggesting a role for inter-EC junctions as a scaffold for MC migration. In the trunk vasculature, MCs derived from mesoderm covered the ventral side of the dorsal aorta (DA), but not the posterior cardinal vein. Furthermore, the MCs migrating from the DA or emerging around intersegmental vessels (ISVs) preferentially covered arterial ISVs rather than venous ISVs, indicating that MCs mostly cover arteries during vascular development. Thus, live imaging and lineage tracing enabled us to clarify precisely how MCs cover the EC tubes and to identify the origins of MCs.

  17. Clarification of mural cell coverage of vascular endothelial cells by live imaging of zebrafish

    Science.gov (United States)

    Ando, Koji; Fukuhara, Shigetomo; Izumi, Nanae; Nakajima, Hiroyuki; Fukui, Hajime; Kelsh, Robert N.; Mochizuki, Naoki

    2016-01-01

    Mural cells (MCs) consisting of vascular smooth muscle cells and pericytes cover the endothelial cells (ECs) to regulate vascular stability and homeostasis. Here, we clarified the mechanism by which MCs develop and cover ECs by generating transgenic zebrafish lines that allow live imaging of MCs and by lineage tracing in vivo. To cover cranial vessels, MCs derived from either neural crest cells or mesoderm emerged around the preformed EC tubes, proliferated and migrated along EC tubes. During their migration, the MCs moved forward by extending their processes along the inter-EC junctions, suggesting a role for inter-EC junctions as a scaffold for MC migration. In the trunk vasculature, MCs derived from mesoderm covered the ventral side of the dorsal aorta (DA), but not the posterior cardinal vein. Furthermore, the MCs migrating from the DA or emerging around intersegmental vessels (ISVs) preferentially covered arterial ISVs rather than venous ISVs, indicating that MCs mostly cover arteries during vascular development. Thus, live imaging and lineage tracing enabled us to clarify precisely how MCs cover the EC tubes and to identify the origins of MCs. PMID:26952986

  18. The roles of vascular endothelial growth factor in bone repair and regeneration.

    Science.gov (United States)

    Hu, Kai; Olsen, Bjorn R

    2016-10-01

    Vascular endothelial growth factor-A (VEGF) is one of the most important growth factors for regulation of vascular development and angiogenesis. Since bone is a highly vascularized organ and angiogenesis plays an important role in osteogenesis, VEGF also influences skeletal development and postnatal bone repair. Compromised bone repair and regeneration in many patients can be attributed to impaired blood supply; thus, modulation of VEGF levels in bones represents a potential strategy for treating compromised bone repair and improving bone regeneration. This review (i) summarizes the roles of VEGF at different stages of bone repair, including the phases of inflammation, endochondral ossification, intramembranous ossification during callus formation and bone remodeling; (ii) discusses different mechanisms underlying the effects of VEGF on osteoblast function, including paracrine, autocrine and intracrine signaling during bone repair; (iii) summarizes the role of VEGF in the bone regenerative procedure, distraction osteogenesis; and (iv) reviews evidence for the effects of VEGF in the context of repair and regeneration techniques involving the use of scaffolds, skeletal stem cells and growth factors. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Endothelial Progenitor Cell Dysfunction in Myelodysplastic Syndromes: Possible Contribution of a Defective Vascular Niche to Myelodysplasia

    Directory of Open Access Journals (Sweden)

    Luciana Teofili

    2015-05-01

    Full Text Available We set a model to replicate the vascular bone marrow niche by using endothelial colony forming cells (ECFCs, and we used it to explore the vascular niche function in patients with low-risk myelodysplastic syndromes (MDS. Overall, we investigated 56 patients and we observed higher levels of ECFCs in MDS than in healthy controls; moreover, MDS ECFCs were found variably hypermethylated for p15INK4b DAPK1, CDH1, or SOCS1. MDS ECFCs exhibited a marked adhesive capacity to normal mononuclear cells. When normal CD34+ cells were co-cultured with MDS ECFCs, they generated significant lower amounts of CD11b+ and CD41+ cells than in co-culture with normal ECFCs. At gene expression profile, several genes involved in cell adhesion were upregulated in MDS ECFCs, while several members of the Wingless and int (Wnt pathways were underexpressed. Furthermore, at miRNA expression profile, MDS ECFCs hypo-expressed various miRNAs involved in Wnt pathway regulation. The addition of Wnt3A reduced the expression of intercellular cell adhesion molecule-1 on MDS ECFCs and restored the defective expression of markers of differentiation. Overall, our data demonstrate that in low-risk MDS, ECFCs exhibit various primary abnormalities, including putative MDS signatures, and suggest the possible contribution of the vascular niche dysfunction to myelodysplasia.

  20. Vascular endothelial growth factor signaling regulates the segregation of artery and vein via ERK activity during vascular development

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Se-Hee [McAllister Heart Institute, Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States); Schmitt, Christopher E.; Woolls, Melissa J. [McAllister Heart Institute, Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States); Yale Cardiovascular Research Center and Section of Cardiovascular Medicine, Dept. of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511 (United States); Holland, Melinda B. [McAllister Heart Institute, Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 (United States); Kim, Jun-Dae [Yale Cardiovascular Research Center and Section of Cardiovascular Medicine, Dept. of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511 (United States); Jin, Suk-Won, E-mail: suk-won.jin@yale.edu [Yale Cardiovascular Research Center and Section of Cardiovascular Medicine, Dept. of Internal Medicine, Yale University School of Medicine, New Haven, CT 06511 (United States)

    2013-01-25

    Highlights: ► VEGF-A signaling regulates the segregation of axial vessels. ► VEGF-A signaling is mediated by PKC and ERK in this process. ► Ectopic activation of ERK is sufficient to rescue defects in vessel segregation. -- Abstract: Segregation of two axial vessels, the dorsal aorta and caudal vein, is one of the earliest patterning events occur during development of vasculature. Despite the importance of this process and recent advances in our understanding on vascular patterning during development, molecular mechanisms that coordinate the segregation of axial vessels remain largely elusive. In this report, we find that vascular endothelial growth factor-A (Vegf-A) signaling regulates the segregation of dorsal aorta and axial vein during development. Inhibition of Vegf-A pathway components including ligand Vegf-A and its cognate receptor Kdrl, caused failure in segregation of axial vessels in zebrafish embryos. Similarly, chemical inhibition of Mitogen-activated protein kinase kinase (Map2k1)/Extracellular-signal-regulated kinases (Erk) and phosphatidylinositol 3-kinases (PI3 K), which are downstream effectors of Vegf-A signaling pathway, led to the fusion of two axial vessels. Moreover, we find that restoring Erk activity by over-expression of constitutively active MEK in embryos with a reduced level of Vegf-A signaling can rescue the defects in axial vessel segregation. Taken together, our data show that segregation of axial vessels requires the function of Vegf-A signaling, and Erk may function as the major downstream effector in this process.

  1. Preservation of vascular DDAH activity contributes to the protection of captopril against endothelial dysfunction in hyperlipidemic rabbits.

    Science.gov (United States)

    Lin, Yuan; Feng, Mei; Lu, Chang-Wu; Lei, Yan-Ping; He, Zhi-Min; Xiong, Yan

    2017-03-05

    Endothelial dysfunction plays a pivotal role in the pathogenesis of atherosclerosis. Endogenous inhibitor of nitric oxide synthase (NOS) asymmetric dimethylarginine (ADMA) has been recognized as an independent risk factor of endothelial dysfunction and the biomarker of atherosclerosis. This study was to investigate whether endogenous ADMA and its metabolic enzyme dimethylarginine dimethylaminohydrolase (DDAH) were involved in mechanisms of captopril protection against endothelial dysfunction in high fat diet feeding rabbits. Half of model rabbits were treated with captopril (10mg/kg/d, i.g.) for 12w. Vascular morphology and serum lipid profiles were detected. Serum ADMA concentration were assayed by high performance liquid chromatography. Recombinant DDAH2 gene adenoviruses were ex vivo transferred to thoracic aortas of high fat diet feeding rabbits. Endothelium-dependent relaxation of aortas response to acetylcholine and DDAH activity were measured. Atherosclerosis was confirmed in high fat diet feeding rabbits by increased serum lipid profiles and morphologic changes of vascular wall. Serum ADMA levels were significantly increased in hyperlipidemic rabbits accompanied with impairment of endothelium-dependent relaxation and inhibition of DDAH activity in thoracic aortas. Captopril treatment not only decreased vascular intima thickening and serum ADMA concentration but also preserved vascular DDAH activity and endothelium-dependent relaxation in hyperlipidemic rabbits without influence on serum lipid profiles. Similar beneficial effects on endothelial function and DDAH activity could be achieved by DDAH2 gene transfection. These results indicated that captopril could protect against injuries of vascular morphology and endothelial function in hyperlipidemic rabbits, the mechanisms may be related to the preservation of DDAH activity and decrease of ADMA accumulation in vascular endothelium. Copyright © 2017. Published by Elsevier B.V.

  2. Inhibition of endothelial activation: a new way to treat cerebral malaria?

    Directory of Open Access Journals (Sweden)

    2005-09-01

    Full Text Available BACKGROUND: Malaria is still a major public health problem, partly because the pathogenesis of its major complication, cerebral malaria (CM, remains incompletely understood. However tumor necrosis factor (TNF is thought to play a key role in the development of this neurological syndrome, as well as lymphotoxin alpha (LT. METHODS AND FINDINGS: Using an in vitro model of CM based on human brain-derived endothelial cells (HBEC-5i, we demonstrate the anti-inflammatory effect of LMP-420, a 2-NH2-6-Cl-9-[(5-dihydroxyboryl-pentyl] purine that is a transcriptional inhibitor of TNF. When added before or concomitantly to TNF, LMP-420 inhibits endothelial cell (EC activation, i.e., the up-regulation of both ICAM-1 and VCAM-1 on HBEC-5i surfaces. Subsequently, LMP-420 abolishes the cytoadherence of ICAM-1-specific Plasmodium falciparum-parasitized red blood cells on these EC. Identical but weaker effects are observed when LMP-420 is added with LT. LMP-420 also causes a dramatic reduction of HBEC-5i vesiculation induced by TNF or LT stimulation, as assessed by microparticle release. CONCLUSION: These data provide evidence for a strong in vitro anti-inflammatory effect of LMP-420 and suggest that targeting host cell pathogenic mechanisms might provide a new therapeutic approach to improving the outcome of CM patients.

  3. Factors secreted by endothelial progenitor cells enhance neurorepair responses after cerebral ischemia in mice.

    Directory of Open Access Journals (Sweden)

    Anna Rosell

    Full Text Available Cell therapy with endothelial progenitor cells (EPCs has emerged as a promising strategy to regenerate the brain after stroke. Here, we aimed to investigate if treatment with EPCs or their secreted factors could potentiate angiogenesis and neurogenesis after permanent focal cerebral ischemia in a mouse model of ischemic stroke. BALB/C male mice were subjected to distal occlusion of the middle cerebral artery, and EPCs, cell-free conditioned media (CM obtained from EPCs, or vehicle media were administered one day after ischemia. Magnetic resonance imaging (MRI was performed at baseline to confirm that the lesions were similar between groups. Immunohistochemical and histological evaluation of the brain was performed to evaluate angio-neurogenesis and neurological outcome at two weeks. CM contained growth factors, such as VEGF, FGF-b and PDGF-bb. A significant increase in capillary density was noted in the peri-infarct areas of EPC- and CM-treated animals. Bielschowsky's staining revealed a significant increase in axonal rewiring in EPC-treated animals compared with shams, but not in CM-treated mice, in close proximity with DCX-positive migrating neuroblasts. At the functional level, post-ischemia forelimb strength was significantly improved in animals receiving EPCs or CM, but not in those receiving vehicle media. In conclusion, we demonstrate for the first time that the administration of EPC-secreted factors could become a safe and effective cell-free option to be considered in future therapeutic strategies for stroke.

  4. Human vascular smooth muscle cells both express and respond to heparin-binding growth factor I (endothelial cell growth factor)

    Energy Technology Data Exchange (ETDEWEB)

    Winkles, J.A.; Friesel, R.; Burgess, W.H.; Howk, R.; Mehlman, T.; Weinstein, R.; Maciag, T.

    1987-10-01

    The control of vascular endothelial and muscle cell proliferation is important in such processes as tumor angiogenesis, wound healing, and the pathogenesis of atherosclerosis. Class I heparin-binding growth factor (HBGF-I) is a potent mitogen and chemoattractant for human endothelial cells in vitro and will induce angiogenesis in vivo. RNA gel blot hybridization experiments demonstrate that cultured human vascular smooth muscle cells, but not human umbilical cells also synthesize an HBGF-I mRNA. Smooth muscle cells also synthesize an HBGF-I-like polypeptide since (i) extract prepared from smooth muscle cells will compete with /sup 125/I-labeled HBGF-I for binding to the HBGF-I cell surface receptor, and (ii) the competing ligand is eluted from heparin-Sepharose affinity resin at a NaCl concentration similar to that required by purified bovine brain HBGF-I and stimulates endothelial cell proliferation in vitro. Furthermore, like endothelial cells, smooth muscle cells possess cell-surface-associated HBGF-I receptors and respond to HBGF-I as a mitogen. These results indicate the potential for an additional autocrine component of vascular smooth muscle cell growth control and establish a vessel wall source of HBGF-I for endothelial cell division in vivo.

  5. Nafamostat Mesilate Inhibits TNF-α-Induced Vascular Endothelial Cell Dysfunction by Inhibiting Reactive Oxygen Species Production.

    Science.gov (United States)

    Kang, Min-Woong; Song, Hee-Jung; Kang, Shin Kwang; Kim, Yonghwan; Jung, Saet-Byel; Jee, Sungju; Moon, Jae Young; Suh, Kwang-Sun; Lee, Sang Do; Jeon, Byeong Hwa; Kim, Cuk-Seong

    2015-05-01

    Nafamostat mesilate (NM) is a serine protease inhibitor with anticoagulant and anti-inflammatory effects. NM has been used in Asia for anticoagulation during extracorporeal circulation in patients undergoing continuous renal replacement therapy and extra corporeal membrane oxygenation. Oxidative stress is an independent risk factor for atherosclerotic vascular disease and is associated with vascular endothelial function. We investigated whether NM could inhibit endothelial dysfunction induced by tumor necrosis factor-α (TNF-α). Human umbilical vein endothelial cells (HUVECs) were treated with TNF-α for 24 h. The effects of NM on monocyte adhesion, vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) protein expression, p38 mitogen-activated protein kinase (MAPK) activation, and intracellular superoxide production were then examined. NM (0.01~100 µg/mL) did not affect HUVEC viability; however, it inhibited the increases in reactive oxygen species (ROS) production and p66shc expression elicited by TNF-α (3 ng/mL), and it dose dependently prevented the TNF-α-induced upregulation of endothelial VCAM-1 and ICAM-1. In addition, it mitigated TNF-α-induced p38 MAPK phosphorylation and the adhesion of U937 monocytes. These data suggest that NM mitigates TNF-α-induced monocyte adhesion and the expression of endothelial cell adhesion molecules, and that the anti-adhesive effect of NM is mediated through the inhibition of p66shc, ROS production, and p38 MAPK activation.

  6. Effect of rosiglitazone in sodium arsenite-induced experimental vascular endothelial dysfunction.

    Science.gov (United States)

    Kaur, Tajpreet; Goel, Rajesh Kumar; Balakumar, Pitchai

    2010-04-01

    The present study has been designed to investigate the effect of rosiglitazone, a peroxisome proliferator activated receptor gamma agonist in sodium arsenite-induced vascular endothelial dysfunction (VED) in rats. The rats were administered sodium arsenite (1.5 mg/kg/day, i.p., 2 weeks) to induce VED. The development of VED was assessed by employing isolated aortic ring preparation and estimating serum nitrite/nitrate concentration. Further, the integrity of the aortic endothelium was assessed histologically using haematoxylin-eosin staining. Moreover, the oxidative stress was assessed by estimating serum thiobarbituric acid reactive substances, aortic reactive oxygen species and reduced form of glutathione. The administration of sodium arsenite produced VED by impairing acetylcholine-induced endothelium dependent relaxation, diminishing the integrity of vascular endothelium and decreasing the serum nitrite/nitrate concentration. In addition, sodium arsenite was noted to produce oxidative stress as it increased serum thiobarbituric acid reactive substances and aortic reactive oxygen species and consequently decreased glutathione. Treatment with rosiglitazone (3 mg/kg/day, p.o., 2 weeks and 5 mg/kg/day, p.o., 2 weeks) significantly prevented sodium arsenite-induced VED by enhancing acetylcholine-induced endothelium dependent relaxation, improving the integrity of vascular endothelium, increasing the nitrite/nitrate concentration and decreasing the oxidative stress. However, the vascular protective effect of rosiglitazone was markedly abolished by co-administration of nitric oxide synthase inhibitor, N-Omega-Nitro-L-Arginine Methyl Ester (L-NAME) (25 mg/kg/day, i.p., 2 weeks). Thus, it may be concluded that rosiglitazone reduces oxidative stress, activates eNOS and enhances the generation of nitric oxide to prevent sodium arsenite-induced VED in rats.

  7. Improvement of endothelial progenitor outgrowth cell (EPOC)-mediated vascularization in gelatin-based hydrogels through pore size manipulation.

    Science.gov (United States)

    Fu, Jiayin; Wiraja, Christian; Muhammad, Hamizan B; Xu, Chenjie; Wang, Dong-An

    2017-08-01

    In addition to chemical compositions, physical properties of scaffolds, such as pore size, can also influence vascularization within the scaffolds. A larger pore has been shown to improve host vascular tissue invasion into scaffolds. However, the influence of pore sizes on vascularization by endothelial cells directly encapsulated in hydrogels remains unknown. In this study, micro-cavitary hydrogels with different pore sizes were created in gelatin-methacrylate hydrogels with dissolvable gelatin microspheres (MS) varying in sizes. The effect of pore sizes on vascular network formation by endothelial progenitor outgrowth cells (EPOCs) encapsulated in hydrogels was then investigated both in vitro and in vivo. When cultured in vitro, vascular networks were formed around pore structures in micro-cavitary hydrogels. The middle pore size supported best differentiation of EPOCs and thus best hydrogel vascularization in vitro. When implantation in vivo, functional connections between encapsulated EPOCs and host vasculature micro-cavitary hydrogels were established. Vascularization in vivo was promoted best in hydrogels with the large pore size due to the increased vascular tissue invasion. These results highlight the difference between in vitro and in vivo culture conditions and indicate that pore sizes shall be designed for in vitro and in vivo hydrogel vascularization respectively. Pore sizes for hydrogel vascularization in vitro shall be middle ones and pore sizes for hydrogel vascularization in vivo shall be large ones. This study reveals that the optimal pore size for hydrogel vascularization in vitro and in vivo is different. The middle pore size supported best differentiation of EPOCs and thus best hydrogel vascularization in vitro, while vascularization in vivo was promoted best in hydrogels with the large pore size due to the increased vascular tissue invasion. These results highlight the difference between in vitro and in vivo culture conditions and indicate that

  8. The impact of vascular endothelial growth factor and basic fibroblast growth factor on cardiac fibroblasts grown under altered gravity conditions

    DEFF Research Database (Denmark)

    Ulbrich, Claudia; Leder, Annekatrin; Pietsch, Jessica

    2010-01-01

    Myocardium is very sensitive to gravitational changes. During a spaceflight cardiovascular atrophy paired with rhythm problems and orthostatic intolerance can occur. The aim of this study was to investigate the impact of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor...

  9. Circulating vascular endothelial growth factor six months after primary surgery as a prognostic marker in patients with colorectal cancer

    DEFF Research Database (Denmark)

    Werther, Kim; Sørensen, Steen; Christensen, Ib Jarle;

    2003-01-01

    High preoperative circulating vascular endothelial growth factor (VEGF) is predictive of poor prognosis in patients with colorectal cancer (CRC). However, postoperative circulating VEGF has not yet been evaluated as a prognostic marker in CRC patients. In 318 consecutive patients who had undergone...

  10. Anti-angiogenesis effect of generation 4 polyamidoamine/vascular endothelial growth factor antisense oligodeoxynucleotide on breast cancer in vitro

    Institute of Scientific and Technical Information of China (English)

    Shan-zhi GU; Xin-han ZHAO; Ling-xiao ZHANG; Li LI; Zhi-yu WANG; Min MENG; Gai-li AN

    2009-01-01

    Objective: To study the effects of the generation 4 polyamidoamine/vascular endothelial growth factor antisense oligodeoxynucleotide (G4PAMAMNEGFASODN) compound on the expressions of vascular endothelial growth factor (VEGF) and its mRNA of breast cancer cells and on the inhibition of vascular endothelial cells. Methods: We examined the morphology of G4PAMAM/VEGFASODN compound and its pH stability, in vitro transfection efficiency and toxicity, and the expressions of VEGF and its mRNA. Methyl thiazolyl tetrazolium assay was used to detect the inhibitory function of the compound on vascular endothelial cells. Results: The compound was about 10 nm in diameter and was homogeneously netlike. From pH 5 to 10, it showed quite a buffered ability. The 48-h transfection rate in the charge ratio of 1:40 was 98.76%, significantly higher than that of the liposome group (P<0.05). None of the transfection products showed obvious toxicity on the cells. The expressions of both VEGF protein and its mRNA after G4PAMAM/VEGFASODN transfection decreased markedly. Conclusion: With a low toxicity, high safety, and high transfection rate, G4PAMAMNEGFASODN could be a promising gene vector. Specifically, it inhibits VEGF gene expression efficiently, laying a basis for further in vivo animal studies.

  11. Gene electro transfer of plasmid encoding vascular endothelial growth factor for enhanced expression and perfusion in the ischemic swine heart.

    Science.gov (United States)

    Hargrave, Barbara; Strange, Robert; Navare, Sagar; Stratton, Michael; Burcus, Nina; Murray, Len; Lundberg, Cathryn; Bulysheva, Anna; Li, Fanying; Heller, Richard

    2014-01-01

    Myocardial ischemia can damage heart muscle and reduce the heart's pumping efficiency. This study used an ischemic swine heart model to investigate the potential for gene electro transfer of a plasmid encoding vascular endothelial growth factor for improving perfusion and, thus, for reducing cardiomyopathy following acute coronary syndrome. Plasmid expression was significantly greater in gene electro transfer treated tissue compared to injection of plasmid encoding vascular endothelial growth factor alone. Higher gene expression was also seen in ischemic versus non-ischemic groups with parameters 20 Volts (ptransfer of plasmid encoding vascular endothelial growth factor had increased perfusion in the area at risk compared to control groups. Troponin and creatine kinase increased across all groups, suggesting equivalent ischemia in all groups prior to treatment. Echocardiography was used to assess ejection fraction, cardiac output, stroke volume, left ventricular end diastolic volume, and left ventricular end systolic volume. No statistically significant differences in these parameters were detected during a 2-week time period. However, directional trends of these variables were interesting and offer valuable information about the feasibility of gene electro transfer of vascular endothelial growth factor in the ischemic heart. The results demonstrate that gene electro transfer can be applied safely and can increase perfusion in an ischemic area. Additional study is needed to evaluate potential efficacy.

  12. Prognostic impact of placenta growth factor and vascular endothelial growth factor A in patients with breast cancer

    DEFF Research Database (Denmark)

    Maae, Else; Olsen, Dorte Aalund; Steffensen, Karina Dahl;

    2012-01-01

    Placenta growth factor (PlGF) and vascular endothelial growth factor A (VEGF-A) are angiogenic growth factors interacting competitively with the same receptors. VEGF-A is essential in both normal and pathologic conditions, but the functions of PlGF seem to be restricted to pathologic conditions...

  13. Prognostic impact of placenta growth factor and vascular endothelial growth factor A in patients with breast cancer

    DEFF Research Database (Denmark)

    Maae, Else; Olsen, Dorte Aalund; Dahl Steffensen, Karina

    2012-01-01

    Background: Placenta growth factor (PlGF) and vascular endothelial growth factor A (VEGF-A) are angiogenic growth factors interacting competitively with the same receptors. VEGF-A is essential in both normal and pathologic conditions, but the functions of PlGF seem to be restricted to pathologic ...

  14. Hypoxia-inducible factor and vascular endothelial growth factor in the neuroretina and retinal blood vessels after retinal ischemia

    DEFF Research Database (Denmark)

    Håkansson, Gisela; Gesslein, Bodil; Gustafsson, Lotta

    2010-01-01

    Retinal ischemia arises from circulatory failure. As the retinal blood vessels are key organs in circulatory failure, our aim was to study the retinal vasculature separately from the neuroretina to elucidate the role of hypoxia-inducible factor (HIF) 1α and 1β and vascular endothelial growth factor...

  15. Endogenous activated protein C limits cancer cell extravasation through sphingosine-1-phosphate receptor 1-mediated vascular endothelial barrier enhancement

    NARCIS (Netherlands)

    G.L. van Sluis; T.M.H. Niers; C.T. Esmon; W. Tigchelaar; D.J. Richel; H.R. Buller; C.J.F. van Noorden; C.A. Spek

    2009-01-01

    Activated protein C (APC) has both anticoagulant activity and direct cell-signaling properties. APC has been reported to promote cancer cell migration/invasion and to inhibit apoptosis and therefore may exacerbate metastasis. Opposing these activities, APC signaling protects the vascular endothelial

  16. Vascular endothelial growth factor is crucial for erythropoietin-induced improvement of cardiac function in heart failure

    NARCIS (Netherlands)

    Westenbrink, B. Daan; Ruifrok, Willem-Peter T.; Voors, Adriaan A.; Tilton, Ronald G.; van Veldhuisen, Dirk J.; Schoemaker, Regien G.; van Gilst, Wiek H.; de Boer, Rudolf A.

    2010-01-01

    We intended to delineate the mechanisms of erythropoietin (EPO)-induced cardiac vascular endothelial growth factor (VEGF) production and to establish if VEGF is crucial for EPO-induced improvement of cardiac performance. The effects of EPO on VEGF expression were studied in cultured cardiac cells an

  17. Vascular endothelial growth factor is crucial for erythropoietin-induced improvement of cardiac function in heart failure

    NARCIS (Netherlands)

    Westenbrink, B. Daan; Ruifrok, Willem-Peter T.; Voors, Adriaan A.; Tilton, Ronald G.; van Veldhuisen, Dirk J.; Schoemaker, Regien G.; van Gilst, Wiek H.; de Boer, Rudolf A.

    2010-01-01

    We intended to delineate the mechanisms of erythropoietin (EPO)-induced cardiac vascular endothelial growth factor (VEGF) production and to establish if VEGF is crucial for EPO-induced improvement of cardiac performance. The effects of EPO on VEGF expression were studied in cultured cardiac cells an

  18. Acute exercise improves endothelial function despite increasing vascular resistance during stress in smokers and nonsmokers.

    Science.gov (United States)

    Rooks, Cherie R; McCully, Kevin K; Dishman, Rod K

    2011-09-01

    The present study examined the effect of acute exercise on flow mediated dilation (FMD) and reactivity to neurovascular challenges among female smokers and nonsmokers. FMD was determined by arterial diameter, velocity, and blood flow measured by Doppler ultrasonography after forearm occlusion. Those measures and blood pressure and heart rate were also assessed in response to forehead cold and the Stroop Color-Word Conflict Test (CWT) before and after 30 min of rest or an acute bout of cycling exercise (∼50% VO₂ peak). Baseline FMD and stress responses were not different between smokers and nonsmokers. Compared to passive rest, exercise increased FMD and decreased arterial velocity and blood flow responses during the Stroop CWT and forehead cold in both groups. Overall, acute exercise improved endothelial function among smokers and nonsmokers despite increasing vascular resistance and reducing limb blood flow during neurovascular stress.

  19. Analysis of Active Components in Salvia Miltiorrhiza Injection Based on Vascular Endothelial Cell Protection

    Directory of Open Access Journals (Sweden)

    Shen Jie

    2014-09-01

    Full Text Available Correlation analysis based on chromatograms and pharmacological activities is essential for understanding the effective components in complex herbal medicines. In this report, HPLC and measurement of antioxidant properties were used to describe the active ingredients of Salvia miltiorrhiza injection (SMI. HPLC results showed that tanshinol, protocatechuic aldehyde, rosmarinic acid, salvianolic acid B, protocatechuic acid and their metabolites in rat serum may contribute to the efficacy of SMI. Assessment of antioxidant properties indicated that differences in the composition of serum powder of SMI caused differences in vascular endothelial cell protection. When bivariate correlation was carried out it was found that salvianolic acid B, tanshinol and protocatechuic aldehyde were active components of SMI because they were correlated to antioxidant properties.

  20. Development of an aptamer-based affinity purification method for vascular endothelial growth factor

    Directory of Open Access Journals (Sweden)

    Maren Lönne

    2015-12-01

    Full Text Available Since aptamers bind their targets with high affinity and specificity, they are promising alternative ligands in protein affinity purification. As aptamers are chemically synthesized oligonucleotides, they can be easily produced in large quantities regarding GMP conditions allowing their application in protein production for therapeutic purposes. Several advantages of aptamers compared to antibodies are described in general within this paper. Here, an aptamer directed against the human Vascular Endothelial Growth Factor (VEGF was used as affinity ligand for establishing a purification platform for VEGF in small scale. The aptamer was covalently immobilized on magnetic beads in a controlled orientation resulting in a functional active affinity matrix. Target binding was optimized by introduction of spacer molecules and variation of aptamer density. Further, salt-induced target elution was demonstrated as well as VEGF purification from a complex protein mixture proving the specificity of protein-aptamer binding.

  1. Vascular endothelial growth factor (VEGF) gene polymorphisms may influence the efficacy of thalidomide in multiple myeloma

    DEFF Research Database (Denmark)

    Andersen, Niels Frost; Vogel, Ulla Birgitte; Klausen, Tobias W;

    2012-01-01

    Vascular endothelial growth factor (VEGF) is a potent proangiogenic factor. Several single nucleotide polymorphisms (SNPs) in the VEGF gene with influence on VEGF expression have been described. In multiple myeloma, VEGF stimulates angiogenesis which is correlated with disease progression...... and prognosis. In this study, we evaluated the association between genetic variations in the VEGF gene in patients with multiple myeloma and time to treatment failure (TTF) after high-dose melphalan and stem cell support (HDT), overall survival (OS) and efficacy of the anti-angiogenic drug thalidomide....... Retrospectively, the SNPs -2,578C>A (rs699947), -460C>T (rs833061), +405G>C (rs2010963) and +936C>T (rs3025039) in the VEGF gene were examined in 348 patients with newly diagnosed multiple myeloma initially treated with HDT, where 176 patients were treated with thalidomide at relapse. None of the examined geno...

  2. The Interleukin-6 and vascular endothelial growth factor in hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    Negar Azarpira

    2012-01-01

    Full Text Available We studied the correlation between changes in the serum levels of vascular endothelial growth factor (VEGF and interleukin-6 (IL-6 with complications such as acute graft versus host disease (aGVHD, veno-occlusive disease (VOD or occurrence of infection after hematopoietic stem cell transplantation (HSCT. Serum VEGF and IL-6 levels were sequentially measured by enzyme-linked immunosorbant assay (ELISA in 35 patients who had undergone HSCT. Serum levels of IL-6 in patients with aGVHD were increased in comparison with patients without aGVHD, but the difference was not statistically significant. Serum levels of VEGF were only increased in patients with aGVHD during the early days after transplantation. No signi-ficantly altered levels of IL-6 and VEGF were observed in patients with VOD or sepsis. These results demonstrate that rising levels of VEGF and IL-6 may be good and specific biomarkers for transplant aGVHD.

  3. Role of vascular endothelial growth factor C in classical Hodgkin lymphoma.

    Science.gov (United States)

    Rueda, Antonio; Olmos, David; Vicioso, Luis; Quero, Cristina; Gallego, Elena; Pajares-Hachero, Bella Isabel; Mendiola, Marta; Casanova, María; Álvarez, Martina; Provencio, Mariano; Alba, Emilio

    2015-05-01

    We performed three different studies to obtain additional data on the biological and prognostic role of vascular endothelial growth factor C (VEGFC) in classical Hodgkin lymphoma (cHL): (1) serum VEGFC levels were measured by enzyme-linked immunosorbent assay in 80 patients; (2) immunohistochemical VEGFC expression in tumor tissue was evaluated using a case-control study in 62 patients; (3) gene expression of VEGFC was investigated in vitro in six cHL cell lines, and was compared with expression in inflammatory lymph nodes. Higher serum VEGFC levels were found in patients with cHL than in healthy volunteers (median, 7675 vs. 1358 pg/mL, p Hodgkin lymphoma cell lines was higher than the mean expression level in inflammatory lymph nodes. Our data suggest that Hodgkin and Reed-Sternberg cells produce VEGFC, and VEGFC expression could be a novel prognostic factor in cHL.

  4. Ramucirumab (IMC-1121B): Monoclonal antibody inhibition of vascular endothelial growth factor receptor-2.

    Science.gov (United States)

    Spratlin, Jennifer

    2011-04-01

    Angiogenesis, a well-recognized characteristic of malignancy, has been exploited more than any other pathway targeted by biologic anti-neoplastic therapies. Vascular endothelial growth factor receptor-2 (VEGFR-2) is the critical receptor involved in malignant angiogenesis with its activation inducing a number of other cellular modifications resulting in tumor growth and metastases. Ramucirumab (IMC-1121B; ImClone Systems Corporation, Branchburg, NJ) is a fully human monoclonal antibody developed to specifically inhibit VEGFR-2. Ramucirumab is currently being investigated in multiple clinical trials across a variety of tumor types. Herein, angiogenesis inhibition in cancer is reviewed and up-to-date information on the clinical development of ramucirumab is presented.

  5. Effects of vascular endothelial growth factor on survival of surgical flaps: a review of experimental studies.

    Science.gov (United States)

    Fang, Taolin; Lineaweaver, William C; Chen, Michael B; Kisner, Carson; Zhang, Feng

    2014-01-01

    Partial or complete necrosis of skin flaps remains a significant problem in plastic and reconstructive surgery. Growth factors have shown promise in improving flap survival through increased angiogenesis and blood supply to the flap. Vascular endothelial growth factor (VEGF) is the most widely investigated and successful one. But the mechanisms of the effects are still not very clear. In the course of a series of experiments, we indicated that tissue survival of surgical flaps could be improved by both preoperative (sustained phase effect) and intraoperative (acute phase effect) application of VEGF. We reviewed both experimental and clinical investigations on the use of VEGF with surgical flaps to summarize the evidence of both phases of VEGF activity in promotion of flaps survival in detail. With the combinations of acute and sustained phases of effects, VEGF protein and gene, VEGF morphologic actions, and VEGF histochemical modulations suggest a pattern of VEGF activity that can be superimposed on classic descriptive mechanisms of tissue survival of flaps.

  6. Analysis of active components in Salvia miltiorrhiza injection based on vascular endothelial cell protection.

    Science.gov (United States)

    Shen, Jie; Yang, Kai; Sun, Caihua; Zheng, Minxia

    2014-09-01

    Correlation analysis based on chromatograms and pharmacological activities is essential for understanding the effective components in complex herbal medicines. In this report, HPLC and measurement of antioxidant properties were used to describe the active ingredients of Salvia miltiorrhiza injection (SMI). HPLC results showed that tanshinol, protocatechuic aldehyde, rosmarinic acid, salvianolic acid B, protocatechuic acid and their metabolites in rat serum may contribute to the efficacy of SMI. Assessment of antioxidant properties indicated that differences in the composition of serum powder of SMI caused differences in vascular endothelial cell protection. When bivariate correlation was carried out it was found that salvianolic acid B, tanshinol and protocatechuic aldehyde were active components of SMI because they were correlated to antioxidant properties.

  7. Prostacyclin production by blood-contacting surfaces of endothelialized vascular prostheses.

    Science.gov (United States)

    Greisler, H P; Klosak, J J; McGurrin, J F; Endean, E D; Ellinger, J; Pozar, J D; Henderson, S C; Kim, D U

    1990-01-01

    This study examines prostacyclin production by blood-contacting surfaces within woven vascular prostheses of polydioxanone (PDS), polyglactin 910 (PG910), or Dacron interposed into rabbit infrarenal aortas. Grafts and normal aortic segments were explanted after 1, 3, and 6 months for pulsatile perfusion with Medium-199 for 60 minutes. Aliquots were removed serially for 6-keto-PGF1 alpha assay. After 30 minutes sodium arachidonate (10 micrograms/ml) was added. Specimens were studied by light microscopy, SEM and TEM. Patency in all three groups exceeded 90%. All three showed re-endothelialization at one month. Normal aorta produced low basal 6-keto-PGF1 alpha with a marked evanescent post arachidonate increase. Dacron did not differ from normal aorta. PG910 and PDS both produced significantly less 6-keto-PGF1 alpha post arachidonate at one month but both increased to normal by three months.

  8. Vascular endothelial growth factor A protein level and gene expression in intracranial meningiomas with brain edema

    DEFF Research Database (Denmark)

    Nassehi, Damoun; Dyrbye, Henrik; Andresen, Morten;

    2011-01-01

    Meningiomas are the second most common primary intracranial tumors in adults. Although meningiomas are mostly benign, more than 50% of patients with meningioma develop peritumoral brain edema (PTBE), which may be fatal because of increased intracranial pressure. Vascular endothelial growth factor....... Forty-three patients had primary, solitary, supratentorial meningiomas with PTBE. In these, correlations in PTBE, edema index, VEGF-A protein, VEGF gene expression, capillary length, and tumor water content were investigated. DNA-branched hybridization was used for measuring VEGF gene expression...... in tissue homogenates prepared from frozen tissue samples. The method for VEGF-A analysis resembled an ELISA assay, but was based on chemiluminescence. The edema index was positively correlated to VEGF-A protein (p = 0.014) and VEGF gene expression (p

  9. THE RELATIONSHIP BETWEEN PERITUMORAL BRAIN EDEMA AND VASCULAR ENDOTHELIAL GROWTH FACTOR EXPRESSION IN PATIENTS WITH MENINGIOMA

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective To determine whether VEGF plays a role in the development of peritumoral brain edema. Methods 50 meningioma patients and their VEGF expression were studied. We took a mono- clonal antibody from mouse to VEGF to stain the tumor cells, the vascular endothelial cells and the interstitial cells. The severity of brain edema was evaluated according to CT or MR scans by the following equation: edema index = Vtumor+edema/Vtumor. The relationship between VEGF expression and edema index was analyzed statisti- cally. Results VEGF was expressed in meningioma tumor cells, which is usually concentrated at the pe- ripheral sites of the tumor. There was a positive linear correlation between the expression and the brain edema index. Conclusion VEGF may play a role in the development of peritumoral brain edema in meningioma patient.

  10. Vascular endothelial growth factor-A is associated with chronic mountain sickness in the Andean population.

    Science.gov (United States)

    Espinoza, Jose R; Alvarez, Giancarlo; León-Velarde, Fabiola; Preciado, Hugo F Ju; Macarlupu, Jose-Luis; Rivera-Ch, Maria; Rodriguez, Jorge; Favier, Judith; Gimenez-Roqueplo, Anne-Paule; Richalet, Jean-Paul

    2014-06-01

    A study of chronic mountain sickness (CMS) with a candidate gene--vascular endothelial growth factor A (VEGFA)--was carried out in a Peruvian population living at high altitude in Cerro de Pasco (4380 m). The study was performed by genotyping of 11 tag SNPs encompassing 2.2 kb of region of VEGFA gene in patients with a diagnosis of CMS (n = 131; 49.1 ± 12.7 years old) and unrelated healthy controls (n = 84; 47.2 ± 13.4 years old). The VEGFA tag SNP rs3025033 was found associated with CMS (p Cerro de Pasco population and HapMap3 population (Fst > 0.36, p < 0.01), suggesting selection is operating on the VEGF gene. Our results suggest that VEGFA is associated with CMS in long-term residents at high altitude in the Peruvian Andes.

  11. RNA interference-mediated gene silencing of vascular endothelial growth factor in colon cancer cells

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    AIM: To inhibit the expression of vascular endothelial growth factor (VEGF) in colon cancer cell line by RNA interference (RNAi). METHODS: Followed the service of E-RNAi, we designed and constructed two kinds of shRNA expression vectors aiming at the VEGF gene, then transfected them into colon cancer HT29 cells by lipofectamineTM 2000. The level of VEGF mRNA was investigated by RT-PCR and Northern blotting. The protein expression of VEGF was observed by immunofluoresence staining and Western blotting. RESULTS: We got two kinds of VEGF specific shRNA expression vectors which could efficiently inhibit the expression of VEGF in HT29 cells. RT-PCR, Northern blotting, immunofluoresence staining and Western blotting showed that inhibition rate for VEGF expression was up to 42%, 89%, 73% and 82%, respectively. CONCLUSION: The expression of VEGF can be inhibited by RNA interference in HT29 cells.

  12. Enhanced Vascular Endothelial Growth Factor Gene Expression in Ischaemic Skin of Critical Limb Ischaemia Patients

    Directory of Open Access Journals (Sweden)

    Silvia Bleda

    2012-01-01

    Full Text Available Objectives. To perform a quantitative analysis of the vascular endothelial growth factor (VEGF gene transcription in the skin of ischemic legs and provide information for VEGF in the pathogenesis in critical limb ischemia (CLI. Methods. Skin biopsies were obtained from 40 patients with CLI. Control samples came from 44 patients with chronic venous disease. VEGF gene expression was analysed using quantitative polymerase chain reaction. Results. Patients with CLI had higher skin VEGF expression than control group (RQ: 1.3 ± 0.1 versus 1, P=0.04. Conclusions. We found an association between ischemic skin and an elevated VEGF expression in legs from patients with CLI. These data support that the mechanism for VEGF upregulation in hypoxia conditions is intact and acts appropriately in the ischaemic limbs from patients with CLI.

  13. Vascular Endothelial Growth Factor Receptor 3 Controls Neural Stem Cell Activation in Mice and Humans

    Directory of Open Access Journals (Sweden)

    Jinah Han

    2015-02-01

    Full Text Available Neural stem cells (NSCs continuously produce new neurons within the adult mammalian hippocampus. NSCs are typically quiescent but activated to self-renew or differentiate into neural progenitor cells. The molecular mechanisms of NSC activation remain poorly understood. Here, we show that adult hippocampal NSCs express vascular endothelial growth factor receptor (VEGFR 3 and its ligand VEGF-C, which activates quiescent NSCs to enter the cell cycle and generate progenitor cells. Hippocampal NSC activation and neurogenesis are impaired by conditional deletion of Vegfr3 in NSCs. Functionally, this is associated with compromised NSC activation in response to VEGF-C and physical activity. In NSCs derived from human embryonic stem cells (hESCs, VEGF-C/VEGFR3 mediates intracellular activation of AKT and ERK pathways that control cell fate and proliferation. These findings identify VEGF-C/VEGFR3 signaling as a specific regulator of NSC activation and neurogenesis in mammals.

  14. Subcellular localization and mechanism of secretion of vascular endothelial growth factor in human skeletal muscle

    DEFF Research Database (Denmark)

    Høier, Birgitte; Prats Gavalda, Clara; Qvortrup, Klaus

    2013-01-01

    The subcellular distribution and secretion of vascular endothelial growth factor (VEGF) was examined in skeletal muscle of healthy humans. Skeletal muscle biopsies were obtained from m.v. lateralis before and after a 2 h bout of cycling exercise. VEGF localization was conducted on preparations...... of teased muscle fibers by transmission electron microscopy (TEM) and confocal microscopy (CM). Muscle interstitial fluid was sampled from microdialysis probes placed in the thigh muscle. TEM and CM analysis revealed two primary sites of localization of VEGF: in vesicles located in the subsarcolemmal...... regions and between the contractile elements within the muscle fibers; and in pericytes situated on the skeletal muscle capillaries. Quantitation of the subsarcolemmal density of VEGF vesicles, calculated on top of myonuclei, in the muscle fibers revealed a ∼50% increase (P...

  15. Tuftsin binds neuropilin-1 through a sequence similar to that encoded by exon 8 of vascular endothelial growth factor.

    Science.gov (United States)

    von Wronski, Mathew A; Raju, Natarajan; Pillai, Radhakrishna; Bogdan, Nancy J; Marinelli, Edmund R; Nanjappan, Palaniappa; Ramalingam, Kondareddiar; Arunachalam, Thangavel; Eaton, Steve; Linder, Karen E; Yan, Feng; Pochon, Sibylle; Tweedle, Michael F; Nunn, Adrian D

    2006-03-03

    Tuftsin, Thr-Lys-Pro-Arg (TKPR), is an immunostimulatory peptide with reported nervous system effects as well. We unexpectedly found that tuftsin and a higher affinity antagonist, TKPPR, bind selectively to neuropilin-1 and block vascular endothelial growth factor (VEGF) binding to that receptor. Dimeric and tetrameric forms of TKPPR had greatly increased affinity for neuropilin-1 based on competition binding experiments. On endothelial cells tetrameric TKPPR inhibited the VEGF(165)-induced autophosphorylation of vascular endothelial growth factor receptor-2 (VEGFR-2) even though it did not directly inhibit VEGF binding to VEGFR-2. Homology between exon 8 of VEGF and TKPPR suggests that the sequence coded for by exon 8 may stabilize VEGF binding to neuropilin-1 to facilitate signaling through VEGFR-2. Given the overlap between processes involving neuropilin-1 and tuftsin, we propose that at least some of the previously reported effects of tuftsin are mediated through neuropilin-1.

  16. Gelatinases, endonuclease and Vascular Endothelial Growth Factor during development and regression of swine luteal tissue

    Directory of Open Access Journals (Sweden)

    Bacci Maria

    2006-11-01

    Full Text Available Abstract Background The development and regression of corpus luteum (CL is characterized by an intense angiogenesis and angioregression accompanied by luteal tissue and extracellular matrix (ECM remodelling. Vascular Endothelial Growth Factor (VEGF is the main regulator of angiogenesis, promoting endothelial cell mitosis and differentiation. After the formation of neovascular tubes, the remodelling of ECM is essential for the correct development of CL, particularly by the action of specific class of proteolytic enzymes known as matrix metalloproteinases (MMPs. During luteal regression, characterized by an apoptotic process and successively by an intense ECM and luteal degradation, the activation of Ca++/Mg++-dependent endonucleases and MMPs activity are required. The levels of expression and activity of VEGF, MMP-2 and -9, and Ca++/Mg++-dependent endonucleases throughout the oestrous cycle and at pregnancy were analyzed. Results Different patterns of VEGF, MMPs and Ca++/Mg++-dependent endonuclease were observed in swine CL during different luteal phases and at pregnancy. Immediately after ovulation, the highest levels of VEGF mRNA/protein and MMP-9 activity were detected. On days 5–14 after ovulation, VEGF expression and MMP-2 and -9 activities are at basal levels, while Ca++/Mg++-dependent endonuclease levels increased significantly in relation to day 1. Only at luteolysis (day 17, Ca++/Mg++-dependent endonuclease and MMP-2 spontaneous activity increased significantly. At pregnancy, high levels of MMP-9 and VEGF were observed. Conclusion Our findings, obtained from a precisely controlled in vivo model of CL development and regression, allow us to determine relationships among VEGF, MMPs and endonucleases during angiogenesis and angioregression. Thus, CL provides a very interesting model for studying factors involved in vascular remodelling.

  17. Coffee polyphenol consumption improves postprandial hyperglycemia associated with impaired vascular endothelial function in healthy male adults.

    Science.gov (United States)

    Jokura, Hiroko; Watanabe, Isamu; Umeda, Mika; Hase, Tadashi; Shimotoyodome, Akira

    2015-10-01

    Epidemiological studies indicate that habitual coffee consumption lowers the risk of diabetes and cardiovascular diseases. Postprandial hyperglycemia is a direct and independent risk factor for cardiovascular diseases. We previously demonstrated that coffee polyphenol ingestion increased secretion of Glucagon-like peptide 1 (GLP-1), which has been shown to exhibit anti-diabetic and cardiovascular effects. We hypothesized coffee polyphenol consumption may improve postprandial hyperglycemia and vascular endothelial function by increasing GLP-1 release and/or reducing oxidative stress. To examine this hypothesis, we conducted a randomized, acute, crossover, intervention study in healthy male adults, measuring blood parameters and flow-mediated dilation (FMD) after ingestion of a meal with or without coffee polyphenol extract (CPE). Nineteen subjects consumed a test meal with either a placebo- or CPE-containing beverage. Blood biomarkers and FMD were measured at fasting and up to 180 minutes postprandially. The CPE beverage led to a significantly lower peak postprandial increase in blood glucose and diacron-reactive oxygen metabolite, and significantly higher postprandial FMD than the placebo beverage. Postprandial blood GLP-1 increase tended to be higher after ingestion of the CPE beverage, compared with placebo. Subclass analysis revealed that the CPE beverage significantly improved postprandial blood GLP-1 response and reduced blood glucose increase in the subjects with a lower insulinogenic index. Correlation analysis showed postprandial FMD was negatively associated with blood glucose increase after ingestion of the CPE beverage. In conclusion, these results suggest that coffee polyphenol consumption improves postprandial hyperglycemia and vascular endothelial function, which is associated with increased GLP-1 secretion and decreased oxidative stress in healthy humans.

  18. Chronic and non-healing wounds: The story of vascular endothelial growth factor.

    Science.gov (United States)

    Zhou, Kehua; Ma, Yan; Brogan, Michael S

    2015-10-01

    The pathophysiology of the chronicity and non-healing status of wounds remains unknown. This paper presents the following hypothesis: abnormal patterns of vascular endothelial growth factor receptors (VEGFRs) are the culprits of wound chronicity and non-healing. More specifically, for patients with poor circulation, the decreased VEGFR-2 level is the cause of poor wound healing; for patients with non-compromised circulation, for example, patients with concurrent chronic wounds and active autoimmune diseases, the increased VEGFR-1 level is related to the non-healing status of wounds. The hypothesis is supported by the following facts. VEGFR-1 is the main contributor for inflammation and VEGFR-2 facilitates angiogenesis; soluble VEGFR-1 (sVEGFR-1) inactivates both VEGFR-1 and VEGFR-2. Patients with auto-immune disease have abnormally increased VEGFR-1 and decreased sVEGFR. Wounds in patients with active autoimmune diseases have poor response to electric stimulation which facilitates chronic wound healing in patients without active autoimmune diseases via increasing vascular endothelial growth factor (VEGF) secretion. Patients with chronic wounds (including diabetic foot ulcers and venous leg ulcers) but no active autoimmune diseases have decreased VEGFR-2 levels. We thus believe that abnormal patterns of VEGFRs are the culprits of wound chronicity and non-healing. For wounds with compromised circulation, VEGFR-2 decrease contributes to its chronicity; whereas for wounds with non-compromised circulation, VEGFR-1 increase is the leading cause of the non-healing status of chronic wounds. Treatments and research in wound care should be tailored to target these changes based on circulation status of wounds. Complete elucidation of changes of VEGFRs in chronic and non-healing wounds will enhance our understandings in tissue healing and thus better our selection of appropriate treatments for chronic and non-healing wounds.

  19. Neuroprotective effect of exogenous vascular endothelial growth factor on rat spinal cord neurons in vitro hypoxia

    Institute of Scientific and Technical Information of China (English)

    DING Xin-min; MAO Bo-yong; JIANG Shu; LI Sheng-fu; DENG Yi-ling

    2005-01-01

    Background Vascular endothelial growth factor (VEGF) is well known as a hypoxia-induced protein. That it markedly increased expression of VEGF and improvement of rat motor function after spinal cord injury suggested that VEGF could play a neuroprotective role in ischaemic tolerance. This study investigated whether vascular endothelial growth factor has direct neuroprotective effects on rat spinal cord neurons. Methods We employed primary cultures of embryonic rat spinal cord neurons, then administrated different concentrations of VEGF164 in the culture medium before hypoxia when the number of neurons was counted and the cell viability was detected by MTT. The neuronal apoptosis and expression of VEGF and its receptor genes were evaluated by terminal deoxynucleotidyl transferase mediated dUTP nick-end labelling (TUNEL) and immunohistochemistry. The VEGFR2/FLK-1 inhibitor, SU1498, was used to confirm whether the neuroprotective effect of VEGF was mediated through VEGFR2/Flk-1 receptors. Result In hypoxic conditions,the number and viability of neurons decreased progressively, while the number of TUNEL-positive cells increased along with the prolongation of hypoxic exposure. When the concentration of VEGF in cell culture medium reached 25 ng/ml, the cell viability increased 11% and neuronal apoptosis reduced to half, this effect was dose dependent and led to an approximately 25% increase in cell viability and about threefold decrease in TUNEL-positive cells at a maximally effective concentration of 100 ng/ml. In normal conditions, VEGF/Flk-1 but not VEGF/Flt-1 gene expressed at a low level: after hypoxia, the expression of VEGF/Flk-1, but not VEGF/Flt-1 was significantly increased. The protective effect of VEGF was blocked by the VEGFR2/Flk-1 receptor tyrosine kinase inhibitor, SU1498. Conclusions VEGF has direct neuroprotective effects on rat spinal cord neurons, which may be mediated in vitro through VEGFR2/Flk-1 receptors.

  20. Inhibition of tubulointerstitial fibrosis by pentoxifylline is associated with improvement of vascular endothelial growth factor expression

    Institute of Scientific and Technical Information of China (English)

    Qiu-gen ZHOU; Fa-lei ZHENG; Fan-fan HOU

    2009-01-01

    Aim: Recent information indicates that pentoxifylline (PTX) has the ability to suppress inflammation and profibrotic cell proliferation. In this study, we investigated the effect of PTX on tubulointerstitial fibrosis and the expression of vascular endothelial growth factor (VEGF) in a rat model of obstructive nephropathy. Methods: Wistar rats with left ureteral ligation were divided into control and PTX-treated groups. The histopathologic degree of tubulointerstitial fibrosis was scored with PAS and Masson-stained sections. The protein and mRNA for vascular endothelial growth factor (VEGF) were semiquantitatively measured with immunohistochemistry and RT-PCR. The pro-tein for transforming growth factor β1 (TGFβ1) and hypoxia-induced factor 1 alpha (HIF-1α) was determined by Western blot. Results: Compared with the control group, PTX treatment reduced fibrosis scores at d 7 and d 14 (P<0.05). The reduction was accompanied by inhibited expression of transforming growth factor-beta 1 (TGFβ1), a key cytokine in tubulointerstitial fibrogenesis (P<0.01). Meanwhile, VEGF protein and mRNA in the kidney were increased in the PTX-treated group com-pared with the control group (P<0.01). PTX up-regulated expression of VEGF mRNA in a dose- and time-dependent man-ner in cultured HK-2 cells (P<0.01). However, expression of HIF-1α (a key transcription factor for VEGF gene expression) was unchanged by PTX treatment. PTX prolonged the half-life of VEGF mRNA by a 1.07-fold increase. Conclusions: PTX inhibited tubulointerstitial fibrosis in a rat model of obstructive nephropathy while preventing loss of VEGF. PTX up-regulated expression of VEGF mRNA through stabilization of its mRNA in cultured renal tubular epithelial cells.

  1. Effects of black raspberry on lipid profiles and vascular endothelial function in patients with metabolic syndrome.

    Science.gov (United States)

    Jeong, Han Saem; Hong, Soon Jun; Lee, Tae-Bum; Kwon, Ji-Wung; Jeong, Jong Tae; Joo, Hyung Joon; Park, Jae Hyoung; Ahn, Chul-Min; Yu, Cheol Woong; Lim, Do-Sun

    2014-10-01

    Black raspberry (Rubus occidentalis) has been known for its anti-inflammatory and anti-oxidant effects. However, short-term effects of black raspberry on lipid profiles and vascular endothelial function have not been investigated in patients with metabolic syndrome. Patients with metabolic syndrome (n = 77) were prospectively randomized into a group with black raspberry (n = 39, 750 mg/day) and a placebo group (n = 38) during a 12-week follow-up. Lipid profiles, brachial artery flow-mediated dilatation (baFMD), and inflammatory cytokines such as IL-6, TNF-α, C-reactive protein, adiponectin, sICAM-1, and sVCAM-1 were measured at the baseline and at the 12-week follow-up. Decreases from the baseline in the total cholesterol level (-22.8 ± 30.4 mg/dL vs. -1.9 ± 31.8 mg/dL, p raspberry than in the placebo group. Increases in baFMD at the 12-week follow-up were significantly greater in the group with black raspberry than in the placebo group (0.33 ± 0.44 mm vs. 0.10 ± 0.35 mm, p raspberry. The use of black raspberry significantly decreased serum total cholesterol level and inflammatory cytokines, thereby improving vascular endothelial function in patients with metabolic syndrome during the 12-week follow-up.

  2. Luteolin inhibits human prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis.

    Directory of Open Access Journals (Sweden)

    Poyil Pratheeshkumar

    Full Text Available Angiogenesis, the formation of new blood vessels from pre-existing vascular beds, is essential for tumor growth, invasion, and metastasis. Luteolin is a common dietary flavonoid found in fruits and vegetables. We studied the antiangiogenic activity of luteolin using in vitro, ex vivo, and in vivo models. In vitro studies using rat aortic ring assay showed that luteolin at non-toxic concentrations significantly inhibited microvessel sprouting and proliferation, migration, invasion and tube formation of endothelial cells, which are key events in the process of angiogenesis. Luteolin also inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay (CAM and matrigel plug assay. Gelatin zymographic analysis demonstrated the inhibitory effect of luteolin on the activation of matrix metalloproteinases MMP-2 and MMP-9. Western blot analysis showed that luteolin suppressed VEGF induced phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT, ERK, mTOR, P70S6K, MMP-2, and MMP-9 in HUVECs. Proinflammatory cytokines such as IL-1β, IL-6, IL-8, and TNF-α level were significantly reduced by the treatment of luteolin in PC-3 cells. Luteolin (10 mg/kg/d significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that luteolin inhibited tumorigenesis by targeting angiogenesis. CD31 and CD34 immunohistochemical staining further revealed that the microvessel density could be remarkably suppressed by luteolin. Moreover, luteolin reduced cell viability and induced apoptosis in prostate cancer cells, which were correlated with the downregulation of AKT, ERK, mTOR, P70S6K, MMP-2, and MMP-9 expressions. Taken together, our findings demonstrate that luteolin inhibits human prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis.

  3. A Simple Bioassay for the Evaluation of Vascular Endothelial Growth Factors.

    Science.gov (United States)

    Stacker, Steven A; Halford, Michael M; Roufail, Sally; Caesar, Carol; Achen, Marc G

    2016-03-15

    The analysis of receptor tyrosine kinases and their interacting ligands involved in vascular biology is often challenging due to the constitutive expression of families of related receptors, a broad range of related ligands and the difficulty of dealing with primary cultures of specialized endothelial cells. Here we describe a bioassay for the detection of ligands to the vascular endothelial growth factor receptor-2 (VEGFR-2), a key transducer of signals that promote angiogenesis and lymphangiogenesis. A cDNA encoding a fusion of the extracellular (ligand-binding) region of VEGFR-2 with the transmembrane and cytoplasmic regions of the erythropoietin receptor (EpoR) is expressed in the factor-dependent cell line Ba/F3. This cell line grows in the presence of interleukin-3 (IL-3) and withdrawal of this factor results in death of the cells within 24 hr. Expression of the VEGFR-2/EpoR receptor fusion provides an alternative mechanism to promote survival and potentially proliferation of stably transfected Ba/F3 cells in the presence of a ligand capable of binding and cross-linking the extracellular portion of the fusion protein (i.e., one that can cross-link the VEGFR-2 extracellular region). The assay can be performed in two ways: a semi-quantitative approach in which small volumes of ligand and cells permit a rapid result in 24 hr, and a quantitative approach involving surrogate markers of a viable cell number. The assay is relatively easy to perform, is highly responsive to known VEGFR-2 ligands and can accommodate extracellular inhibitors of VEGFR-2 signaling such as monoclonal antibodies to the receptor or ligands, and soluble ligand traps.

  4. Effects of Salvia miltiorrhiza on Hemorheology and vascular endothelial function in patients with unstable angina pectoris

    Institute of Scientific and Technical Information of China (English)

    Shi-Lian Chen; Sheng-Bing Huang

    2016-01-01

    Objective:To investigate the effect of Salvia miltiorrhiza (SM) on vascular endothelial function and hemorheology in patients with unstable angina pectoris (UAP).Methods: A total of 60 cases of UAP patients from October 2014 to October 2015 as the research object, randomly divided into treatment group and control group; the two groups were treated with conventional bed rest, ECG monitoring, oxygen inhalation, application of nitroglycerin, beta blockers, aspirin and antiplatelet, statin therapy, the treatment group based on the use of salvianolate 200 mg+5% glucose 250 mL (neutralization amount of 0.9% sodium chloride was used in patients with diabetes or glucose insulin) intravenous drip, 1 times/d, two groups were treated for 2 weeks; the two groups before and after treatment and take venous blood in the morning fasting peripheral blood viscosity, plasma viscosity, measured by automatic blood rheometer (low and middle shear and high shear rate), hematocrit and erythrocyte aggregation index, serum endothelin (ET) and nitric oxide (NO) level was measured by nitrate reductase Set.Results:after the treatment, the treatment group, the plasma viscosity, whole blood viscosity (low shear, cut and high shear rate), red blood cell hematocrit and red blood cell aggregation index decreased than the control group, there is statistical significance; after treatment, in treatment group, the serum NO level, et reduce degree is significantly better than the contrast group, there is statistical significance.Conclusion: Salvia miltiorrhiza can effectively improve blood rheology, improve microcirculation, regulate vascular endothelial function, effectively reduce the risk of cardiovascular events in UAP patients, it is worthy of clinical application.

  5. Association Between Peripheral Vascular Endothelial Function and Progression of Open-Angle Glaucoma.

    Science.gov (United States)

    Liu, Chun-Hsiu; Su, Wei-Wen; Shie, Shian-Sen; Cheng, Shih-Tsung; Su, Cheng-Wen; Ho, Wang-Jing

    2016-03-01

    The aim of the study is to evaluate the relationship between Humphrey visual field progression and peripheral vascular endothelial function in patients with open-angle glaucoma (OAG), assessed by noninvasive endothelium-dependent flow-mediated vasodilation (FMD).Forty OAG patients, among which 22 had normal-tension glaucoma (NTG) and 18 had primary open-angle glaucoma (POAG) were enrolled. Each enrolled patient underwent a thorough ophthalmological examination including the Humphrey visual field test and measurement of FMD via high-resolution 2-dimensional ultrasonographic imaging of the brachial artery. Blood samples were evaluated for biochemistry and lipid profiles as well as levels of high-sensitivity C-reactive protein (hsCRP). The annual change of threshold sensitivity of the visual field in each test location were analyzed with pointwise linear regression. The correlation between long-term visual field progression and FMD was evaluated.A mean follow-up of 7.47 ± 1.84 years revealed a faster progression rate over the superior visual field in all 40 OAG patients (superior field -0.24 ± 0.67 dB/y, inferior field -0.10 ± 0.59 dB/y, P = 0.37). However, only the annual sensitivity change of the inferior peripheral field showed correlation with baseline FMD. There was no significant difference in the change slope of visual field between NTG and POAG patients.A correlation between baseline brachial artery FMD and visual field progression was observed in the inferior peripheral field in patients with NTG and POAG. This result suggests that peripheral vascular endothelial dysfunction may be related to glaucoma progression.

  6. Induction of angiogenesis by implantation of encapsulated primary myoblasts expressing vascular endothelial growth factor.

    Science.gov (United States)

    Springer, M L; Hortelano, G; Bouley, D M; Wong, J; Kraft, P E; Blau, H M

    2000-01-01

    We previously demonstrated that intramuscular implantation of primary myoblasts engineered to express vascular endothelial growth factor (VEGF) constitutively resulted in hemangioma formation and the appearance of VEGF in the circulation. To investigate the potential for using allogeneic myoblasts and the effects of delivery of VEGF-expressing myoblasts to non-muscle sites, we have enclosed them in microcapsules that protect allogeneic cells from rejection, yet allow the secretion of proteins produced by the cells. Encapsulated mouse primary myoblasts that constitutively expressed murine VEGF164, or encapsulated negative control cells, were implanted either subcutaneously or intraperitoneally into mice. Upon subcutaneous implantation, capsules containing VEGF-expressing myoblasts gave rise to large tissue masses at the implantation site that continued to grow and were composed primarily of endothelial and smooth muscle cells directly surrounding the capsules, and macrophages and capillaries further away from the capsules. Similarly, when injected intraperitoneally, VEGF-producing capsules caused significant localized inflammation and angiogenesis within the peritoneum, and ultimately led to fatal intraperitoneal hemorrhage. Notably, however, VEGF was not detected in the plasma of any mice. We conclude that encapsulated primary myoblasts persist and continue to secrete VEGF subcutaneously and intraperitoneally, but that the heparin-binding isoform VEGF164 exerts localized effects at the site of production. VEGF secreted from the capsules attracts endothelial and smooth muscle cells in a macrophage-independent manner. These results, along with our previous results, show that the mode and site of delivery of the same factor by the same engineered myoblasts can lead to markedly different outcomes. Moreover, the results confirm that constitutive delivery of high levels of VEGF is not desirable. In contrast, regulatable expression may lead to efficacious, safe, and

  7. Grape seed extract inhibits angiogenesis via suppression of the vascular endothelial growth factor receptor signaling pathway.

    Science.gov (United States)

    Wen, Wei; Lu, Jianming; Zhang, Keqiang; Chen, Shiuan

    2008-12-01

    Blockade of angiogenesis is an important approach for cancer treatment and prevention. Vascular endothelial growth factor (VEGF) is one of the most critical factors that induce angiogenesis and has thus become an attractive target for antiangiogenesis treatment. However, most current anti-VEGF agents often cause some side effects when given chronically. Identification of naturally occurring VEGF inhibitors derived from diet would be one alternative approach with an advantage of known safety. Grape seed extract (GSE), a widely used dietary supplement, is known to have antitumor activity. In this study, we have explored the activity of GSE on VEGF receptor and angiogenesis. We found that GSE could directly inhibit the kinase activity of purified VEGF receptor 2, a novel activity of GSE that has not been characterized. GSE could also inhibit the VEGF receptor/mitogen-activated protein kinase-mediated signaling pathway in endothelial cells. As a result, GSE could inhibit VEGF-induced endothelial cell proliferation and migration as well as sprout formation from aorta ring. In vivo assay further showed that GSE could inhibit tumor growth and tumor angiogenesis of MDA-MB-231 breast cancer cells in mice. Consistent with the in vitro data, GSE treatment of tumor-bearing mice led to concomitant reduction of blood vessel density and phosphorylation of mitogen-activated protein kinase. Depletion of polyphenol with polyvinylpyrrolidone abolished the antiangiogenic activity of GSE, suggesting a water-soluble fraction of polyphenol in GSE is responsible for the antiangiogenic activity. Taken together, this study indicates that GSE is a well-tolerated and inexpensive natural VEGF inhibitor and could potentially be useful in cancer prevention or treatment.

  8. EFFECTS OF PROLONGED ENDURANCE EXERCISE ON VASCULAR ENDOTHELIAL AND INFLAMMATION MARKERS

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    Haemi Jee

    2012-12-01

    Full Text Available Systemic inflammation has been found in association with vascular endothelial function for clinical implications including exercise-induced pathology. However, information on the relationship between the exercise-related inflammatory responses and endothelial function is limited. This study aimed to investigate the effects of prolonged endurance exercise on the expression of selected soluble adhesion molecules and inflammatory markers. Twenty- four middle-aged males participating in a 308 km ultra-marathon were recruited in this study. Venous blood was collected at baseline, 100 km, 200 km, and 308 km for the analysis of sVCAM-1, sE- selectin, leukocytes, hs-CRP, CK, and TNF-α. Significant increases of sVCAM-1, sE-selectin, and leukocytes were observed at 100 km. sVCAM-1 had the greatest significant increase at 100 km. In addition, sVCAM-1 was significantly associated with the running speed and leukocytes. sE-selectin was significantly associated with leukocytes, hs-CRP, TNF-α, and CK. Delayed rises in hs-CRP and CK were observed at 200 km. TNF-α fluctuated throughout the race with a significant increase at 308 km. Delayed onset of hs-CRP and continuously increased sE-selectin suggest anti-inflammatory responses to suppress pro-inflammatory markers such as TNF-α. Prolonged repetition of muscle contraction may have released delayed CK and significant rise in TNF-α toward the end of the race. The present study demonstrated an activation of the surrogate markers of endothelial dysfunction in relationship to exercise intensity and leukocyte trafficking without a significant activation of the inflammatory responses. Thus, alteration of the endothelium may be related to increased blood flow and shear stress put upon the endothelium in response to increased oxygen demand on the heart

  9. Olive oil compounds inhibit vascular endothelial growth factor receptor-2 phosphorylation

    Energy Technology Data Exchange (ETDEWEB)

    Lamy, Sylvie, E-mail: lamy.sylvie@uqam.ca; Ouanouki, Amira; Béliveau, Richard; Desrosiers, Richard R.

    2014-03-10

    Vascular endothelial growth factor (VEGF) triggers crucial signaling processes that regulate tumor angiogenesis and, therefore, represents an attractive target for the development of novel anticancer therapeutics. Several epidemiological studies have confirmed that abundant consumption of foods from plant origin is associated with reduced risk of developing cancers. In the Mediterranean basin, the consumption of extra virgin olive oil is an important constituent of the diet. Compared to other vegetable oils, the presence of several phenolic antioxidants in olive oil is believed to prevent the occurrence of a variety of pathological processes, such as cancer. While the strong antioxidant potential of these molecules is well characterized, their antiangiogenic activities remain unknown. The aim of this study is to investigate whether tyrosol (Tyr), hydroxytyrosol (HT), taxifolin (Tax), oleuropein (OL) and oleic acid (OA), five compounds contained in extra virgin olive oil, can affect in vitro angiogenesis. We found that HT, Tax and OA were the most potent angiogenesis inhibitors through their inhibitory effect on specific autophosphorylation sites of VEGFR-2 (Tyr951, Tyr1059, Tyr1175 and Tyr1214) leading to the inhibition of endothelial cell (EC) signaling. Inhibition of VEGFR-2 by these olive oil compounds significantly reduced VEGF-induced EC proliferation and migration as well as their morphogenic differentiation into capillary-like tubular structures in Matrigel. Our study demonstrates that HT, Tax and OA are novel and potent inhibitors of the VEGFR-2 signaling pathway. These findings emphasize the chemopreventive properties of olive oil and highlight the importance of nutrition in cancer prevention. - Highlights: • We investigated five compounds contained in extra virgin olive oil on angiogenesis. • Hydroxytyrosol, taxifolin and oleic acid are the best angiogenesis inhibitors. • Olive oil compounds affect endothelial cell functions essential for

  10. Interleukin-1beta induced vascular permeability is dependent on induction of endothelial tissue factor (TF) activity.

    Science.gov (United States)

    Puhlmann, Markus; Weinreich, David M; Farma, Jeffrey M; Carroll, Nancy M; Turner, Ewa M; Alexander, H Richard

    2005-09-30

    IL-1beta is a pleotropic cytokine that may mediate increased procoagulant activity and permeability in endothelial tissue during inflammatory conditions. The procoagulant effects of IL-1beta are mediated through induction of tissue factor (TF) but its alterations on vascular permeability are not well characterized. We found that IL-1beta induced a rapid and dose-dependent increase in TF activity in human umbilical vein endothelial cells (ECs) under routine culture conditions. However, IL-1beta caused a rapid and marked increase in permeability across confluent EC monolayers using a two-compartment in vitro model only in the presence of factor VIII-deficient plasma that was completely abrogated by neutralizing anti-TF antibody pre-treatment. In vitro permeability was associated with loss of EC surface expression of VE-cadherin and contraction of F-actin cytoskeletal elements that resulted in EC intercellular gap formation. These data demonstrate that IL-1beta induces marked changes in permeability across activated endothelium via a TF dependent mechanism and suggest that modulation of TF activity may represent a strategy to treat various acute and chronic inflammatory conditions mediated by this cytokine.

  11. Interleukin-1β induced vascular permeability is dependent on induction of endothelial Tissue Factor (TF activity

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    Turner Ewa M

    2005-09-01

    Full Text Available Abstract IL-1β is a pleotropic cytokine that may mediate increased procoagulant activity and permeability in endothelial tissue during inflammatory conditions. The procoagulant effects of IL-1β are mediated through induction of tissue factor (TF but its alterations on vascular permeability are not well characterized. We found that IL-1β induced a rapid and dose-dependent increase in TF activity in human umbilical vein endothelial cells (ECs under routine culture conditions. However, IL-1β caused a rapid and marked increase in permeability across confluent EC monolayers using a two-compartment in vitro model only in the presence of factor VIII-deficient plasma that was completely abrogated by neutralizing anti-TF antibody pre-treatment. In vitro permeability was associated with loss of EC surface expression of VE-cadherin and contraction of F-actin cytoskeletal elements that resulted in EC intercellular gap formation. These data demonstrate that IL-1β induces marked changes in permeability across activated endothelium via a TF dependent mechanism and suggest that modulation of TF activity may represent a strategy to treat various acute and chronic inflammatory conditions mediated by this cytokine.

  12. Proinflammatory Cytokines Increase Vascular Endothelial Growth Factor Expression in Alveolar Epithelial Cells

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    James P. Maloney

    2015-01-01

    Full Text Available Vascular endothelial growth factor (VEGF is an endothelial permeability mediator that is highly expressed in lung epithelium. In nonlung cells proinflammatory cytokines have been shown to increase VEGF expression, but their effects on lung epithelium remain unclear. We hypothesized that increases in alveolar epithelial cell VEGF RNA and protein expression occur after exposure to proinflammatory cytokines. We tested this using human alveolar epithelial cells (A549 stimulated with 5 proinflammatory cytokines. VEGF RNA expression was increased 1.4–2.7-fold in response to IL-1, IL-6, IL-8, TNF-α, or TGF-β over 6 hours, with TGF-β having the largest response. TNF-α increased VEGF RNA as early as 1 hour. A mix of IL-1, IL-6, and IL-8 had effects similar to IL-1. TNF-α increased protein expression as early as 4 hours and had a sustained effect at 16 hours, whereas IL-1 did not increase protein expression. Only VEGF165 was present in cultured A549 cells, yet other isoforms were seen in human lung tissue. Increased expression of VEGF in alveolar epithelial cells occurs in response to proinflammatory cytokines. Increased VEGF expression likely contributes to the pathogenesis of inflammatory lung diseases and to the angiogenic phenotype of lung cancer, a disease typically preceded by chronic inflammation.

  13. Platelet and endothelial adhesion on fluorosurfactant polymers designed for vascular graft modification.

    Science.gov (United States)

    Tang, Chad; Kligman, Faina; Larsen, Coby C; Kottke-Marchant, Kandice; Marchant, Roger E

    2009-02-01

    A prominent failure mechanism of small diameter expanded polytetrafluoroethylene (ePTFE) vascular grafts is platelet-mediated thrombosis. We have designed a surface modification for ePTFE consisting of a self-assembling fluorosurfactant polymer (FSP) bearing biologically active ligands, including adhesive peptides and polysaccharide moieties. The goal of this biomimetic construct is to improve graft hemocompatibility by promoting rapid surface endothelialization, whereas minimizing platelet adhesion. Here we present a direct comparison of platelet and endothelial cell (EC) adhesion to FSPs containing one of three cell-adhesion peptides: cyclic Arg-Gly-Asp-D-Phe-Glu (cRGD), cyclic *Cys-Arg-Arg-Glu-Thr-Ala-Trp-Ala-Cys* (cRRE, *denotes disulfide bond cyclization), linear Gly-Arg-Gly-Asp-Ser-Pro-Ala (RGD), or a polysaccharide moiety: oligomaltose (M-7), later designed to prevent nonspecific protein adhesion. Measurements of soluble peptide-integrin binding indicated that cRRE exhibits very low affinity for the alpha(IIb)beta(3) platelet fibrinogen receptor. Static and dynamic adhesion of washed, activated platelets on FSP-modified surfaces revealed that M-7 and cRRE promote significantly less platelet adhesion compared to RGD and cRGD FSPs, whereas EC adhesion was similar on all peptide FSPs and minimal on M-7 FSP. These results illustrate the potential for ligands presented in a FSP surface modification to selectively adhere ECs with limited platelet attachment.

  14. (-)-Epigallocatechin gallate inhibits TNF-α-induced PAI-1 production in vascular endothelial cells.

    Science.gov (United States)

    Cao, Yanli; Wang, Difei; Wang, Xiaoli; Zhang, Jin; Shan, Zhongyan; Teng, Weiping

    2013-11-01

    : (-)-Epigallocatechin gallate (EGCG), the major catechin derived from green tea, reduces the incidence of cardiovascular diseases such as atherosclerosis. Plasminogen activator inhibitor-1 (PAI-1) accelerates thrombus formation upon ruptured atherosclerotic plaques. However, it is not known whether or not EGCG inhibits PAI-1 production induced by tumor necrosis factor-α (TNF-α) in endothelial cells. This study tested the hypothesis that EGCG might have an inhibitory effect on PAI-1 production induced by TNF-α. Human umbilical vein endothelial cells were cultured and incubated with TNF-α and/or EGCG. The expression of p-extracellular regulated protein kinases (p-ERK1/2) and tumor necrosis factor receptor (TNFR1) protein was quantified by Western blotting, and PAI-1 levels were measured by enzyme-linked immunosorbent assay. The results showed that TNF-α increased PAI-1 production in both a dose-dependent and time-dependent manner, and EGCG prevented TNF-α-mediated PAI-1 production and reduced phosphorylation of ERK1/2. The ERK1/2 inhibitor, PD98059 (20 μmol/L), downregulated TNF-α-induced PAI-1 expression 57.69 ± 2.46% (P TNF-α stimulation resulted in a significant decrease in TNFR1, an effect that was abolished by pretreatment with EGCG. These results suggest that EGCG could provide vascular benefits in inflammatory cardiovascular diseases such as decreased thrombus formation associated with ruptured atherosclerotic plaques.

  15. Bisphenol A Disrupts Transcription and Decreases Viability in Aging Vascular Endothelial Cells

    Science.gov (United States)

    Ribeiro-Varandas, Edna; Pereira, H. Sofia; Monteiro, Sara; Neves, Elsa; Brito, Luísa; Boavida Ferreira, Ricardo; Viegas, Wanda; Delgado, Margarida

    2014-01-01

    Bisphenol A (BPA) is a widely utilized endocrine disruptor capable of mimicking endogenous hormones, employed in the manufacture of numerous consumer products, thereby interfering with physiological cellular functions. Recent research has shown that BPA alters epigenetic cellular mechanisms in mammals and may be correlated to enhanced cellular senescence. Here, the effects of BPA at 10 ng/mL and 1 µg/mL, concentrations found in human samples, were analyzed on HT29 human colon adenocarcinona cell line and Human Umbilical Vein Endothelial Cells (HUVEC). Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) transcriptional analysis of the Long Interspersed Element-1 (LINE-1) retroelement showed that BPA induces global transcription deregulation in both cell lines, although with more pronounced effects in HUVEC cells. Whereas there was an increase in global transcription in HT29 exclusively after 24 h of exposure, this chemical had prolonged effects on HUVEC. Immunoblotting revealed that this was not accompanied by alterations in the overall content of H3K9me2 and H3K4me3 epigenetic marks. Importantly, cell viability assays and transcriptional analysis indicated that prolonged BPA exposure affects aging processes in senescent HUVEC. To our knowledge this is the first report that BPA interferes with senescence in primary vascular endothelial cells, therefore, suggesting its association to the etiology of age-related human pathologies, such as atherosclerosis. PMID:25207595

  16. [Study on FAK regulation of migration of vascular endothelial cells depending upon focal adhesion proteins].

    Science.gov (United States)

    Gao, Min; Liu, Xiaoheng; Sun, Heng; Ren, Hongyi; Wang, Lijuan; Shen, Yang

    2013-06-01

    Tumor angiogenesis induced by vascular endothelial cells (VECs) migration is a necessary condition for tumor growth and metastasis. The purpose of this study is to investigate the effect of focal adhesion kinase (FAK) inhibitor (50nmol/mL) on the adhesion and migration of endothelial cells(ECs) and the expression of focal adhesion proteins vinculin, talin and paxillin. Scratch wound migration assay was performed to examine the effect of FAK inhibitor with 50nmol/mL on ECs migration at 0, 5, 10, 30, 60 and 120min, respectively. And immunofluorescence analysis was performed to detect the expression of F-actin in ECs treated with FAK inhibitor within 2h. Western blot was carried out to determine the effect of FAK inhibitor on expression of vinculin, talin and paxillin proteins. The results showed that the migration distance and the expression of F-actin in ECs treated with FAK inhibitor decreased significantly compared with that of the controls, and the level of vinculin showed no significant difference with increasing of treated time of FAK inhibitor. However, the talin and paxillin showed an identical decreasing tendency in 5-10min, but slowly going up in 30min and then after subsequently decreasing. The results of this study proved that blocking phosphorylation of FAK could inhibit VECs adhesion and migration by downregulating focal adhesion proteins so that it may inhibit tumor angiogenesis. This may provide a new approach for tumor therapy.

  17. A polymer nanoparticle with engineered affinity for a vascular endothelial growth factor (VEGF165)

    Science.gov (United States)

    Koide, Hiroyuki; Yoshimatsu, Keiichi; Hoshino, Yu; Lee, Shih-Hui; Okajima, Ai; Ariizumi, Saki; Narita, Yudai; Yonamine, Yusuke; Weisman, Adam C.; Nishimura, Yuri; Oku, Naoto; Miura, Yoshiko; Shea, Kenneth J.

    2017-07-01

    Protein affinity reagents are widely used in basic research, diagnostics and separations and for clinical applications, the most common of which are antibodies. However, they often suffer from high cost, and difficulties in their development, production and storage. Here we show that a synthetic polymer nanoparticle (NP) can be engineered to have many of the functions of a protein affinity reagent. Polymer NPs with nM affinity to a key vascular endothelial growth factor (VEGF165) inhibit binding of the signalling protein to its receptor VEGFR-2, preventing receptor phosphorylation and downstream VEGF165-dependent endothelial cell migration and invasion into the extracellular matrix. In addition, the NPs inhibit VEGF-mediated new blood vessel formation in Matrigel plugs in vivo. Importantly, the non-toxic NPs were not found to exhibit off-target activity. These results support the assertion that synthetic polymers offer a new paradigm in the search for abiotic protein affinity reagents by providing many of the functions of their protein counterparts.

  18. Docosapentaenoic acid (22:5, n-3) suppressed tube-forming activity in endothelial cells induced by vascular endothelial growth factor.

    Science.gov (United States)

    Tsuji, Masako; Murota, Se-itsu; Morita, Ikuo

    2003-05-01

    It is generally accepted that n-3 polyunsaturated fatty acids have beneficial effects on vascular homeostasis. Among the several functions of endothelial cells, angiogenesis contributes to tumor growth, inflammation, and microangiopathy. We have already demonstrated that eicosapentaenoic acid (EPA, 20:5, n-3) suppressed angiogenesis. In this paper, we examined the effect of docosapentaenoic acid (DPA, 22:5, n-3), an elongated metabolite of EPA, on tube-forming activity in bovine aortic endothelial cells (BAE cells) incubated between type I collagen gels. The pretreatment of BAE cells with DPA suppressed tube-forming activity induced by vascular endothelial growth factor (VEGF). The effect of DPA was stronger than those of EPA and docosahexaenoic acid (22:6, n-3). The migrating activity of endothelial cells stimulated with VEGF was also suppressed by DPA pretreatment. The treatment of BAE cells with DPA caused the suppression of VEGF receptor-2 (VEGFR-2, the kinase insert domain-containing receptor, KDR) expression in both plastic dish and collagen gel cultures. These data indicate that DPA has a potent inhibitory effect on angiogenesis through the suppression of VEGFR-2 expression.

  19. Osteoblast-conditioned media influence the expression of E-selectin on bone-derived vascular endothelial cells.

    Science.gov (United States)

    Makuch, Lauren A; Sosnoski, Donna M; Gay, Carol V

    2006-08-01

    Breast cancer cells frequently metastasize to the ends of long bones, ribs and vertebrae, structures which contain a rich microvasculature that is closely juxtaposed to metabolically active trabecular bone surfaces. This study focuses on the effects of osteoblast secretions on the surface presentation of adhesive proteins on skeletal vascular endothelial cells. Vascular endothelial cells were isolated from trabecular bone regions of the long bones of 7-week-old Swiss Webster mice and also from the central marrow cavity where trabecular bone is absent. Both types of endothelial cells were placed in culture for 7 days, then exposed 24 h to conditioned media from MC3T3-E1 osteoblasts. Conditioned medium (CM) from two different stages of osteoblast development were tested: (1) from immature MC3T3-E1 cells cultured for 5-7 days and (2) from mature MC3T3-E1 cells cultured for 28-30 days. The immature osteoblasts were in a stage of rapid proliferation; the mature osteoblasts formed a matrix that mineralized. Following exposure to the conditioned media, the vascular cells were exposed to anti-P-selectin, anti-E-selectin, anti-ICAM-1, and anti-VCAM-1 to detect the corresponding adhesive proteins on their surfaces. Breast cancer cells are known to bind to these adhesive proteins. Of the four proteins evaluated, E-selectin was consistently found on more cell surfaces (approximately 30%) of bone-derived vascular endothelial cells (BVECs) when exposed to the immature CM whereas vascular endothelial cells from marrow (MVECs) did not show this response to either immature CM or mature CM. These studies suggest that the BVEC blood vessels near immature bone cells express more surface adhesive protein that could enhance entrapment and extravasation of breast cancer cells. Once cancer cells have undergone extravasation into marrow adjacent to bone, they could be readily attracted to nearby bone surfaces.

  20. A theoretical framework for determining cerebral vascular function and heterogeneity from dynamic susceptibility contrast MRI.

    Science.gov (United States)

    Digernes, Ingrid; Bjørnerud, Atle; Vatnehol, Svein Are S; Løvland, Grete; Courivaud, Frédéric; Vik-Mo, Einar; Meling, Torstein R; Emblem, Kyrre E

    2017-06-01

    Mapping the complex heterogeneity of vascular tissue in the brain is important for understanding cerebrovascular disease. In this translational study, we build on previous work using vessel architectural imaging (VAI) and present a theoretical framework for determining cerebral vascular function and heterogeneity from dynamic susceptibility contrast magnetic resonance imaging (MRI). Our tissue model covers realistic structural architectures for vessel branching and orientations, as well as a range of hemodynamic scenarios for blood flow, capillary transit times and oxygenation. In a typical image voxel, our findings show that the apparent MRI relaxation rates are independent of the mean vessel orientation and that the vortex area, a VAI-based parameter, is determined by the relative oxygen saturation level and the vessel branching of the tissue. Finally, in both simulated and patient data, we show that the relative distributions of the vortex area parameter as a function of capillary transit times show unique characteristics in normal-appearing white and gray matter tissue, whereas tumour-voxels in comparison display a heterogeneous distribution. Collectively, our study presents a comprehensive framework that may serve as a roadmap for in vivo and per-voxel determination of vascular status and heterogeneity in cerebral tissue.

  1. Vascular Endothelial Growth Factor-Related Pathways in Hemato-Lymphoid Malignancies

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    Michael Medinger

    2010-01-01

    Full Text Available Angiogenesis is essential for malignant tumor growth. This has been documented for solid tumors, and there is an emerging evidence suggesting that tumor progression of hematolymphoid malignancies also depends on the induction of new blood vessel formation. The most important proangiogenic agent is vascular endothelial growth factor (VEGF, activating VEGF receptors 1 and 2. The available data on angiogenesis in hemato-lymphoid malignancies, such as acute leukemias, myelodysplastic syndromes, myeloproliferative neoplasms, multiple myeloma, and lymphomas, point towards the significance of autocrine and paracrine VEGF-mediated effects for proliferation and survival of leukemia/lymphoma cells in addition to tumor vascularization. Antiangiogenic strategies have become an important therapeutic modality for solid tumors. Several antiangiogenic agents targeting VEGF-related pathways are also being utilized in clinical trials for the treatment of hemato-lymphoid malignancies, and in some instances these pathways have emerged as promising therapeutic targets. This review summarizes recent advances in the basic understanding of the role of angiogenesis in hemato-lymphoid malignancies and the translation of such basic findings into clinical studies.

  2. Effect of Ginkgo Leaf Extract on Vascular Endothelial Function in Patients with Early Stage Diabetic Nephropathy

    Institute of Scientific and Technical Information of China (English)

    LI Xu-sheng; ZHENG Wei-ying; LOU Shi-xian; LU Xiao-wen; YE Shang-he

    2009-01-01

    Objective: To explore the effect of ginkgo leaf extract (GLE) on vascular endothelial function (VEF) in patients with early stage diabetic nephropathy (DN). Methods: Sixty-four patients were randomized equally by a randomzing digital table into two groups, the treated group and the control group. They were all treated for 8 weeks with conventional therapy for diabetes, but GLE tablets were given to the treated group additionally. Changes in VEF were estimated before and after treatment by ultrasonic examination of the brachial artery. In the meantime, changes in plasma levels of the von Willebrand factor (vWF), nitric oxide (NO) and endothelin-1 (ET-1) were observed as well. Results: The brachial arterial endothelium dependent dilating function in the treated group increased from 4.91±2.31% before treatment to 6.78±3.89% after treatment (P0.05). Conclusion: GLE could decrease the plasma level of vWF, raise the plasma NO level and improve the endothelium dependent vascular dilating function in DN patients.

  3. Impact of Enzymatic Degradation of the Endothelial Glycocalyx on Vascular Permeability in an Awake Hamster Model

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    S. A. Landsverk

    2012-01-01

    Full Text Available Background. The inside of the endothelium is covered by a glycocalyx layer, and enzymatic degradation of this layer induces vascular leakage ex vivo. We hypothesized that enzymatic degrading of the glycocalyx in an in vivo, whole body model, would induce plasma leakage and affect the microcirculation. Methods. Golden Syrian hamsters were divided into an enzyme (hyaluronidase and a control group. Mean arterial pressure (MAP, heart rate (HR, hematocrit (Hct, base excess (BE, and plasma volume were obtained before, 45 and 120 min after enzyme/saline treatment. Plasma volume was evaluated by the distribution volume of indocyanine green and the microcirculation by functional capillary density (FCD. The enzymatic effect was determined by measuring plasma levels of hyaluronan (HA. Results. There were no differences in MAP, HR, Hct, and BE between the two groups. Enzyme treatment did not induce changes in plasma volume but reduced FCD. There was a 50–100-fold increase in plasma HA, but no relationship was found between HA levels and plasma volume or FCD. Conclusion. Vascular leakage was not confirmed in an in vivo, whole body model after degradation of the endothelial glycocalyx. The microcirculation was affected, but no relationship between plasma levels of HA and FCD was seen.

  4. Exercise Training Could Improve Age-Related Changes in Cerebral Blood Flow and Capillary Vascularity through the Upregulation of VEGF and eNOS

    Directory of Open Access Journals (Sweden)

    Sheepsumon Viboolvorakul

    2014-01-01

    Full Text Available This study aimed to investigate the effect of exercise training on age-induced microvascular alterations in the brain. Additionally, the association with the protein levels of vascular endothelial growth factor (VEGF and endothelial nitric oxide synthase (eNOS was also assessed. Male Wistar rats were divided into four groups: sedentary-young (SE-Young, n=5, sedentary aged (SE-Aged, n=8, immersed-aged (IM-Aged, n=5, and exercise trained-aged (ET-Aged, 60 minutes/day and 5 days/week for 8 weeks, n=8 rats. The MAPs of all aged groups, SE-Aged, IM-Aged, and ET-Aged, were significantly higher than that of the SE-Young group. The regional cerebral blood flow (rCBF in the SE-Aged and IM-Aged was significantly decreased as compared to SE-Young groups. However, rCBF of ET-Aged group was significantly higher than that in the IM-Aged group (P<0.05. Moreover, the percentage of capillary vascularity (%CV and the levels of VEGF and eNOS in the ET-Aged group were significantly increased compared to the IM-Aged group (P<0.05. These results imply that exercise training could improve age-induced microvascular changes and hypoperfusion closely associated with the upregulation of VEGF and eNOS.

  5. By Different Cellular Mechanisms, Lymphatic Vessels Sprout by Endothelial Cell Recruitment Whereas Blood Vessels Grow by Vascular Expansion

    Science.gov (United States)

    Parsons-Wingerter, Patricia; McKay, Terri L.; Leontiev, Dmitry; Condrich, Terence K.; DiCorleto, Paul E.

    2005-01-01

    The development of effective vascular therapies requires the understanding of all modes of vessel formation contributing to vasculogenesis, angiogenesis (here termed hemangiogenesis) and lymphangiogenesis. We show that lymphangiogenesis proceeds by blind-ended vessel sprouting via recruitment of isolated endothelial progenitor cells to the tips of growing vessels, whereas hemangiogenesis occurs by non-sprouting vessel expansion from the capillary network, during middevelopment in the quail chorioallantoic membrane (CAM). Blood vessels expanded out of capillaries that displayed transient expression of alpha smooth muscle actin (alphaSMA), accompanied by mural recruitment of migratory progenitor cells expressing SMA. Lymphatics and blood vessels were identified by confocal/fluorescence microscopy of vascular endothelial growth factor (VEGF) receptors VEGFR-1 and VEGFR-2, alphaSMA (expressed on CAM blood vessels but not on lymphatics), homeobox transcription factor Prox-1 (specific to CAM lymphatic endothelium), and the quail hematopoetic/vascular marker, QH-1. Expression of VEGFR-1 was highly restricted to blood vessels (primarily capillaries). VEGFR-2 was expressed intensely in isolated hematopoietic cells, lymphatic vessels and moderately in blood vessels. Prox-1 was absent from endothelial progenitor cells prior to lymphatic recruitment. Although vascular endothelial growth factor-165 (VEGF(sub 165)) is a key regulator of numerous cellular processes in hemangiogenesis and vasculogenesis, the role of VEGF(sub 165) in lymphangiogenesis is less clear. Exogenous VEGF(sub 165) increased blood vessel density without changing endogenous modes of vascular/lymphatic vessel formation or marker expression patterns. However, VEGF(sub 165) did increase the frequency of blood vascular anastomoses and strongly induced the antimaturational dissociation of lymphatics from blood vessels, with frequent formation of homogeneous lymphatic networks.

  6. Herpes Zoster oftálmico e posterior acidente vascular cerebral: relato de caso

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    Carlos A. M. Guerreiro

    1984-12-01

    Full Text Available Um caso de acidente vascular cerebral (AVC 14 semanas após a instalação de herpes zoster oftálmico (HZO é apresentado. A tomografia computadorizada craniana documentou comprometimento em território de artéria cerebral média ipsilateral ao HZO. O diagnóstico de probabilidade é o de arterite por herpes zoster com posterior trombose. Os autores reviram a literatura e enfatizam o longo intervalo entre o HZO e a instalação da hemiplegia. Citam as novas drogas antivirais que tornam esta causa de AVC potencialmente passível de ser prevenida.

  7. Salvianolic acid B inhibits platelets-mediated inflammatory response in vascular endothelial cells.

    Science.gov (United States)

    Xu, Shixin; Zhong, Aiqin; Bu, Xiaokun; Ma, Huining; Li, Wei; Xu, Xiaomin; Zhang, Junping

    2015-01-01

    Salvianolic acid B (SAB) is a hydrophilic component isolated from the Chinese herb Salviae miltiorrhizae, which has been used clinically for the treatment of ischemic cardiovascular and cerebrovascular diseases. Platelets-mediated vascular inflammatory response contributes to the initiation and progression of atherosclerosis. In this paper, we focus on the modulating effects of SAB on the inflammatory reaction of endothelial cells triggered by activated platelets. Human umbilical vein endothelial cells (EA.hy926) were pretreated with SAB followed by co-culture with ADP-activated platelets. Adhesion of platelets to endothelial cells was observed by amorphological method. The activation of nuclear factor-kappa B was evaluated by NF-κB p65 nuclear translocation and the protein phosphorylation. A determination of the pro-inflammatory mediators (ICAM-1, IL-1β, IL-6, IL-8, MCP-1) mRNA and protein were also conducted. In addition, the inhibitory effects of SAB on platelets activation were also evaluated using a platelet aggregation assay and assessing the release level of soluble P-selectin. The results showed that SAB dose-dependently inhibited ADP- or α-thrombin-induced human platelets aggregation in platelet rich plasma (PRP) samples, and significantly decreased soluble P-selectin release from both agonists stimulated washed platelets. It was also found that pre-treatment with SAB reduced adhesion of ADP-activated platelets to EA.hy926 cells and inhibited NF-κB activation. In addition, SAB significantly suppressed pro-inflammatory mediators mRNA and protein in EA.hy926 cells in a dose-dependent manner. These results indicated that, in addition to its inhibitory effects on platelets activation, SAB was able to attenuate platelets-mediated inflammatory responses in endothelial cells even if the platelets had already been activated. This anti-inflammatory effect was related to the inhibition of NF-κB activation. Our findings suggest that SAB may be a potential

  8. Treatment of metastatic colorectal carcinomas by systemic inhibition of vascular endothelial growth factor signaling in mice

    Institute of Scientific and Technical Information of China (English)

    Volker Schmitz; Miroslaw Kornek; Tobias Hilbert; Christian Dzienisowicz; Esther Raskopf; Christian Rabe; Tilman Sauerbruch; Cheng Qian; Wolfgang H Caselmann

    2005-01-01

    AIM: Tumor angiogenesis has been shown to be promoted by vascular endothelial growth factor (VEGF) via stimulating endothelial cell proliferation, migration, and survival.Blockade of VEGF signaling by different means has been demonstrated to result in reduced tumor growth and suppression of tumor angiogenesis in distinct tumor entities.Here, we tested a recombinant adenovirus, AdsFlt1-3,that encodes an antagonistically acting fragment of the VEGF receptor 1 (Flt-1), for systemic antitumor effects in pre-established subcutaneous CRC tumors in mice.METHODS: Murine colorectal carcinoma cells (CT26) were inoculated subcutaneously into Balb/c mice forin vivo studies. Tumor size and survival were determined. 293cell line was used for propagation of the adenoviral vectors.Human lung cancer line 4549 and human umbilical vein endothelial cells were transfected forin vitro experiments.RESULTS: Infection of tumor cells with AdsFlt1-3 resulted in protein secretion into cell supernatant, demonstrating correct vector function. As expected, the secreted sFlt1-3 protein had no direct effect on CT26 tumor cell proliferation in vitro, but endothelial cell function was inhibited by about 46% as compared to the AdLacZ control in a tube formation assay. When AdsFlt1-3 (5×109 PFU/animal) was applied to tumor bearing mice, we found a tumor inhibition by 72% at d 12 after treatment initiation. In spite of these antitumoral effects, the survival time was not improved.According to reduced intratumoral microvessel density in AdsFlt1-3-treated mice, the antitumor mechanism can be attributed to angiostatic vector effects. We did not detect increased systemic VEGF levels after AdsFlt1-3 treatment and liver toxicity was low as judged by serum alanine aminotransferase determination.CONCLUSION: In this study we confirmed the value of a systemic administration of AdsFlt1-3 to block VEGF signaling as antitumor therapy in an experimental metastatic colorectal carcinoma model in mice.

  9. Changes in vascular reactivity following administration of isoproterenol for 1 week: a role for endothelial modulation.

    Science.gov (United States)

    Davel, Ana Paula C; Kawamoto, Elisa Mitiko; Scavone, Cristoforo; Vassallo, Dalton V; Rossoni, Luciana V

    2006-07-01

    1. The aim of this study was to assess the effects of treatment with isoproterenol (ISO, 0.3 mg kg-1 day-1, s.c.) for 7 days on the vascular reactivity of rat-isolated aortic rings. Additionally, potential mechanisms underlying the changes that involved the endothelial modulation of contractility were investigated. 2. Treatment with ISO induced cardiac hypertrophy without changes in haemodynamic parameters. Aortic rings from ISO-treated rats showed an increase in the contraction response to phenylephrine (PHE) and serotonin, but did not change relaxations produced by acetylcholine or isoproterenol. Removal of the endothelium increased the responses to PHE in both groups. However, this procedure was less effective in ISO-treated as compared with control rats. Endothelial cell removal abolished the increase in the response to PHE in ISO-treated rats. The presence of Nomega-nitro-L-arginine methyl ester shifted the concentration-response curve to PHE to the left in both groups of rats. However, this effect was more pronounced in the ISO group. In addition, aminoguanidine (50 microM) potentiated the actions of PHE only in the ISO group. ISO treatment increased nitric oxide synthase (NOS) activity and neuronal NOS and endothelial NOS protein expression in the aorta. 3. Neither losartan (10 microM) nor indomethacin (10 microM) abolished the effects of ISO on the actions of PHE. Superoxide dismutase (SOD, 150 U ml-1) and L-arginine (5 mM), but neither catalase (300 U ml-1) nor apocynin (100 microM), blocked the effect of ISO treatment. In addition, we observed an increase in superoxide anion levels as measured by ethidium bromide fluorescence and of copper and zinc superoxide dismutase protein expression in ISO-treated rats. 4. In conclusion, our data suggest that ISO treatment alters the endothelial cell-mediated modulation of the contraction to PHE in rat aorta. The increased maximal response of PHE seems to be due to an increase in superoxide anion generation, which

  10. Fetal origins of adult vascular dysfunction in mice lacking endothelial nitric oxide synthase.

    Science.gov (United States)

    Longo, Monica; Jain, Venu; Vedernikov, Yuri P; Bukowski, Radek; Garfield, Robert E; Hankins, Gary D; Anderson, Garland D; Saade, George R

    2005-05-01

    Epidemiological studies have shown increased incidence of hypertension and coronary artery disease in growth-restricted fetuses during their adult life. A novel animal model was used to test the hypothesis regarding the role of an abnormal uterine environment in fetal programming of adult vascular dysfunction. Mice lacking a functional endothelial nitric oxide synthase (NOS3-/-KO, where KO is knockout) and wild-type (WT) mice (NOS3+/+WT) were crossbred to produce homozygous NOS3-/-KO, maternally derived heterozygous (NOS3+/-mat, mother with NOS3 deficiency), paternally derived heterozygous (NOS3+/-pat, normal mother), and NOS3+/+WT litters. Number of fetuses per litter was smaller in NOS3-/-KO and NOS3+/-mat compared with NOS3+/-pat and NOS3+/+WT mice. Adult female mice from these litters (7-8 wk old) were killed, and ring preparations of carotid and mesenteric arteries were mounted in a wire myograph to evaluate the passive and reactive vascular characteristics. Slope of the length-tension plot (a measure of vascular compliance) was increased, and optimal diameter (as calculated by Laplace equation) was decreased in NOS3-/-KO and NOS3+/-mat compared with NOS3+/-pat and NOS3+/+WT mice. Acetylcholine caused vasorelaxation in NOS3+/-pat and NOS3+/+WT and contraction in NOS3-/-KO and NOS3+/-mat mice. Responses to phenylephrine and Ca2+ were increased in NOS3-/-KO and NOS3+/-mat compared with NOS3+/-pat and NOS3+/+WT mice. Relaxation to isoproterenol was decreased in NOS3-/-KO and NOS3+/-mat vs. NOS3+/-pat and NOS3+/+WT mice. Abnormalities in the passive and reactive in vitro vascular properties seen in NOS+/-mat that developed in a NOS3-deficient maternal/uterine environment compared with the genetically identical NOS3+/-pat mice that developed in a normal environment are the first direct evidence in support of a role for uterine environment in determining vascular function in later life.

  11. Wall shear stress effects on endothelial-endothelial and endothelial-smooth muscle cell interactions in tissue engineered models of the vascular wall.

    Directory of Open Access Journals (Sweden)

    Dalit Shav

    Full Text Available Vascular functions are affected by wall shear stresses (WSS applied on the endothelial cells (EC, as well as by the interactions of the EC with the adjacent smooth muscle cells (SMC. The present study was designed to investigate the effects of WSS on the endothelial interactions with its surroundings. For this purpose we developed and constructed two co-culture models of EC and SMC, and compared their response to that of a single monolayer of cultured EC. In one co-culture model the EC were cultured on the SMC, whereas in the other model the EC and SMC were cultured on the opposite sides of a membrane. We studied EC-matrix interactions through focal adhesion kinase morphology, EC-EC interactions through VE-Cadherin expression and morphology, and EC-SMC interactions through the expression of Cx43 and Cx37. In the absence of WSS the SMC presence reduced EC-EC connectivity but produced EC-SMC connections using both connexins. The exposure to WSS produced discontinuity in the EC-EC connections, with a weaker effect in the co-culture models. In the EC monolayer, WSS exposure (12 and 4 dyne/cm(2 for 30 min increased the EC-EC interaction using both connexins. WSS exposure of 12 dyne/cm(2 did not affect the EC-SMC interactions, whereas WSS of 4 dyne/cm(2 elevated the amount of Cx43 and reduced the amount of Cx37, with a different magnitude between the models. The reduced endothelium connectivity suggests that the presence of SMC reduces the sealing properties of the endothelium, showing a more inflammatory phenotype while the distance between the two cell types reduced their interactions. These results demonstrate that EC-SMC interactions affect EC phenotype and change the EC response to WSS. Furthermore, the interactions formed between the EC and SMC demonstrate that the 1-side model can simulate better the arterioles, while the 2-side model provides better simulation of larger arteries.

  12. Oligomeric Amyloid-β Peptide on Sialylic Lewisx–Selectin Bonding at Cerebral Endothelial Surface

    Directory of Open Access Journals (Sweden)

    Sholpan Askarova

    2014-12-01

    Full Text Available Introduction: Alzheimer’s disease (AD is a chronic neurodegenerative disorder, which affects approximately 10% of the population aged 65 and 40% of people over the age 80. Currently, AD is on the list of diseases with no effective treatment. Thus, the study of molecular and cellular mechanisms of AD progression is of high scientific and practical importance. In fact, dysfunction of the blood-brain barrier (BBB plays an important role in the onset and progression of the disease. Increased deposition of amyloid b peptide (Aβ in cerebral vasculature and enhanced transmigration of monocytes across the BBB are frequently observed in AD brains and are some of the pathological hallmarks of the diseases. Since the transmigration of monocytes across the BBB is both a mechanical and a biochemical process, the expression of adhesion molecules and mechanical properties of endothelial cells are the critical factors that require investigation.Methods: Because of recent advances in the biological applications of atomic force microscopy (AFM, we applied AFM with cantilever tips bio-functionalized by sLex in combination with the advanced immunofluorescent microscopy (QIM to study the direct effects of Aβ42 oligomers on the selectins expression, actin polymerization, and cellular mechanical and adhesion properties in cerebral endothelial cells (mouse bEnd3 line and primary human CECs and find a possible way to attenuate these effects. Results: QIM results showed that Aβ42 increased the expressions of P-selectin on the cell surface and enhanced actin polymerization. Consistent with our QIM results, AFM data showed that Aβ42 increased the probability of cell adhesion with sLex-coated cantilever and cell stiffness. These effects were counteracted by lovstatin, a cholesterol-lowering drug.  Surprisingly, the apparent rupture force of sLex-selectin bonding was significantly lower after treatment with Aβ42, as compared with the control (i.e. no treatment

  13. Effects of cerebrolysin on moderate cognitive impairments in cerebral vascular insufficiency (a clinical-electrophysiological study).

    Science.gov (United States)

    Damulin, I V; Koberskaya, N N; Mkhitaryan, E A

    2008-07-01

    The efficacy of treatment with cerebrolysin was studied in 40 patients with cerebral vascular insufficiency. Cerebrolysin (20 daily i.v. infusions of 10 ml in 200 ml of physiological saline) was found to be an effective means of treating this group of patients. Courses of cerebrolysin treatment decreased the severity of memory and attention impairments, improving the overall cognitive status of the patients. Clinical observations and neuropsychological testing were supported by electrophysiological results, in terms of the P300 cognitive evoked potential. The effects of treatment at the doses used here were delayed and were seen three months after completion of treatment.

  14. A distensibilidade da aorta prediz o acidente vascular cerebral em pacientes hipertensos

    OpenAIRE

    Telmo Pereira; João Maldonado; Liliana Pereira; Jorge Conde

    2013-01-01

    FUNDAMENTO: A doença cardiovascular continua a ser principal causa de morte nos países desenvolvidos e não é inteiramente prevista por fatores de risco clássicos. O aumento da rigidez arterial constitui um importante determinante de morbidade e mortalidade cardiovascular. OBJETIVO: Avaliar se a velocidade da onda de pulso prediz a ocorrência de acidente vascular cerebral (AVC) em pacientes hipertensos. MÉTODOS: Estudo de coorte, observacional, prospetivo, multicêntrico, incluindo 1.133 pacien...

  15. PERFIL DA DISFAGIA APÓS UM ACIDENTE VASCULAR CEREBRAL: UMA REVISÃO INTEGRATIVA

    OpenAIRE

    CARINA TEIXEIRA PAIXÃO; LOLITA DOPICO DA SILVA; FLAVIA GIRON CAMERINI

    2010-01-01

    Este artículo trata de disfagia decurrente de una enfermedad vascular cerebral (EVC). El objetivo fue determinar el perfil de las publicaciones acerca de la disfagia en pacientes víctimas de EVC. Investigación de revisión integradora que usó los mismos descriptores en las bases Medline, Scielo e Lilacs, seleccionando 17 artículos entre 1998 a 2008. Los datos fueron analizados a partir de las categorías correspondientes a los enfoques de las publicaciones encontradas. Los resultados muestran d...

  16. Crioterapia e cinesioterapia no membro superior espástico no acidente vascular cerebral

    OpenAIRE

    Correia,Andreza de Cássia Souza; Silva,Jonathan Danilo Santos; Silva,Lícia Vasconcelos Carvalho da; Oliveira,Daniella Araujo de; Cabral,Etenildo Dantas

    2010-01-01

    INTRODUÇÃO: A espasticidade no paciente com sequela de Acidente Vascular Cerebral (AVC) acarreta limitações nas atividades de vida diária e torna-se um importante fator de risco para o desenvolvimento de deformidades estáticas quando não tratada. OBJETIVO: Avaliar o efeito da crioterapia associada à cinesioterapia no padrão postural flexor e no grau de espasticidade do membro superior de pacientes com AVC. METODOLOGIA: Participaram desta pesquisa sete voluntários que apresentavam espasticidad...

  17. Factores asociados a crisis epilépticas en pacientes con enfermedad vascular cerebral aguda.

    OpenAIRE

    Salirrosas-Alegría, Cristopher; Médico residente de Psiquiatría, Instituto Nacional de Salud Mental Honorio Delgado - Hideyo Noguchi. Facultad de Medicina Alberto Hurtado, Universidad Peruana Cayetano Heredia. Lima.; Pereda-Vásquez, Firdusi; Profesor Principal de Neurología Clínica y de Semiología Neurológica. Facultad de Medicina. Universidad Nacional de Trujillo. Coordinador Académico del Residentado de Neurología de la Facultad de Medicina. Universidad Nacional de Trujillo. Trujillo, Perú.

    2013-01-01

    Objetivos: Determinar la asociación entre el tipo de enfermedad vascular cerebral (EVC), la extensión de la lesióncerebral, la presencia de cardiopatía isquémica y/o fibrilación auricular; y las crisis epilépticas en pacientes con EVCaguda. Material y métodos: Se realizó un estudio descriptivo, de tipo casos y controles. Se estudiaron a los pacientesque presentaron crisis epilépticas luego de la EVC. Las variables fueron: crisis epilépticas, tipo de EVC, cardiopatíaisquémica, fibrilación auri...

  18. Vascular endothelial function and oxidative stress are related to dietary niacin intake among healthy middle-aged and older adults.

    Science.gov (United States)

    Kaplon, Rachelle E; Gano, Lindsey B; Seals, Douglas R

    2014-01-15

    We tested the hypothesis that vascular endothelial function and oxidative stress are related to dietary niacin intake among healthy middle-aged and older adults. In 127 men and women aged 48-77 yr, brachial artery flow-mediated dilation (FMD) was positively related to dietary niacin intake [%change (Δ): r = 0.20, P niacin intake (≥ 22 mg/day, NHANES III), FMD was 25% greater than in subjects with below-average intake (P niacin intake (above vs. below average) was an independent predictor of FMD (%Δ: β = 1.8; mmΔ: β = 0.05, both P niacin intake (r = -0.23, P niacin intake (48 ± 2 vs. 57 ± 2 mg/dl, P niacin intake (P 0.05, n = 20). In endothelial cells sampled from the brachial artery of a subgroup, dietary niacin intake was inversely related to nitrotyrosine, a marker of peroxynitrite-mediated oxidative damage (r = -0.30, P niacin intake [nitrotyrosine: 0.39 ± 0.05 vs. 0.56 ± 0.07; NADPH oxidase: 0.38 ± 0.05 vs. 0.53 ± 0.05 (ratio to human umbilical vein endothelial cell control), both P niacin intake is associated with greater vascular endothelial function related to lower systemic and vascular oxidative stress among healthy middle-aged and older adults.

  19. Src Kinase becomes preferentially associated with the VEGFR, KDR/Flk-1, following VEGF stimulation of vascular endothelial cells

    Directory of Open Access Journals (Sweden)

    Wang Jing

    2002-12-01

    Full Text Available Abstract Background The cytoplasmic tyrosine kinase, Src, has been found to play a