UCL University College London Eprints
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Activation of endogenous c-Src or a related tyrosine kinase by intracellular (pY)EEI peptide increases voltage-operated calcium channel currents in rabbit ear artery cells. - Wijetunge, S; Hughes, AD
The effect of activation of endogenous c-Src tyrosine kinase by (pY)EEI peptide was examined on voltage-operated calcium channel (VOC) currents in arterial smooth muscle cells. In single rabbit ear artery cells intracellular application of (pY)EEI peptide increased calcium channel currents. Inactive, non-phosphorylated YEEI peptide had no effect on currents. Peptide-A, a 21 amino acid inhibitor of c-Src inhibited currents and prevented the effect of (pY)EEI peptide on calcium channel currents. These results indicate that activation of intrinsic c-Src increases VOC and support a role for c-Src in the regulation of VOC in vascular smooth muscle cells.
Retinal vascular network architecture in low-birth-weight men - Chapman, N; Mohamudally, A; Cerutti, A; Stanton, A; Sever, P; Hughes, A; Thom, S; Sayer, AA; Cooper, C; Barker, D; Rauf, A; Evans, J; Wormald, R
Background. Low birth weight is associated with hypertension and increased cardiovascular mortality, but the mechanism of this association is not known. Hypertension is accompanied by abnormalities of the microvasculature including rarefaction. Objective. To test the hypothesis that low birth weight is associated with an alteration in microvascular architecture. Design. A stratified random sample of 100 men aged 64-74 years was selected from a cohort of men whose birth weights were known, They were of relatively high or low birth weight ('high' ≤ 3700 g, 'low' ≤ 3200 g) and high or low systolic blood pressure (high ≤ 160 mmHg, low...
Toward retinal vessel parameterisation - Gao, X; Hughes, AJ; Stanton, A; Chapman, N; Thom, S; Bharath, AA
The reliable measurement of retinal vessel geometry in ordinary red-free fundus photographs is a challenging issue. Quite apart from refractive effects which can distort absolute measures, the existence of the central light reflex poses some interesting problems in vessel modelling and segmentation. One aim of our research is to obtain subpixel vessel width precision from digitised retinal photographs. For this purpose, we require a reasonable physical and mathematical model for the vessel intensity profile. In this paper, we review physical principles behind the image formation, leading to a twin Gaussian model. We test 4 non-linear parametric models based on Gaussian...
Differential effects of lovastatin on mitogen induced calcium influx in human cultured vascular smooth muscle cells. - Clunn, GF; Lymn, JS; Schachter, M; Hughes, AD
1. In this study the effect of lovastatin, an inhibitor of cholesterol and isoprenoid synthesis, on the rises in intracellular calcium concentration ([Ca2+]i) induced by platelet derived growth factor BB (PDGF-BB), angiotensin II (AII), low density lipoproteins (LDL) and foetal calf serum (FCS) was examined in human cultured vascular smooth muscle cells (VSMC) from saphenous vein. Changes in [Ca2+]i were measured in cell suspensions by the Ca2+ sensitive probe, fura 2. 2. Incubation with lovastatin for 24-26 h markedly reduced the peak rise and sustained phase of [Ca2+]i elevation in response to PDGF-BB but the responses to AII, LDL and...
Action of ryanodine on neurogenic responses in rat isolated mesenteric small arteries. - Garcha, RS; Hughes, AD
1. Rat mesenteric (approximately 250 microns) were set up in a single-channel isometric myograph designed to allow with 6 microM fura-2AM for 2 h and simultaneous recordings of neurogenic contraction (force) and intracellular calcium [Ca2+]i were obtained. In other experiments, arteries were loaded with 1 microCi ml-1 [3H]-noradrenaline (NA) for 30 min in order to measure release of [3H]-NA in response to field stimulation to examine whether ryanodine directly inhibited neuronal release of NA. 2. Arteries were activated by single intermittent field stimulation or continuously to excite intrinsic sympathetic nerves, or by cumulative addition of noradrenaline (1 nM-10 microM) to...
Inhibition of proliferation by heparin and expression of p53 in cultured human vascular smooth muscle cells. - Sawhney, N; Patel, MK; Schachter, M; Hughes, AD
Human vascular smooth muscle cells (HVSMC) cultured from restenotic lesions are resistant to inhibition of proliferation by heparin. We examined if altered expression of p53 protein might be related to this phenomenon. HVSMC were cultured from saphenous vein and p53 protein levels examined using immunocytochemistry, and by immunoprecipitation with antibodies specific for wild-type or mutant conformations followed by SDS PAGE and immunoblotting. Inhibition of proliferation by heparin was measured in 14-day growth assays. Elevated levels of p53 were found in five out of 41 HVSMC strains. The accumulated p53 protein was not precipitated by a mutant conformation-specific anti-p53 antibody in...
Direct vascular effects of furosemide in humans - Hughes, AD; Smits, P; Pickkers, P; Dormans, TPJ; Russel, FGM; Thien, T; Schaper, N
Background: In humans, hemodynamic changes observed within minutes after systemic administration of furosemide are often referred to as direct vasoactivity. However, these immediate changes do not per se imply a direct vascular effect. We examined the genuine direct vascular effects of furosemide on the human forearm vascular bed and dorsal hand vein. Methods and Results: Forearm blood flow in response to infusion of increasing dosages of furosemide into the brachial artery was recorded by venous occlusion plethysmography. Local plasma concentrations of furosemide reached a maximum of 234±40 μg/mL during the highest infused dose but did not significantly affect the ratio...
Platelet-derived growth factor beta-receptors can both promote and inhibit chemotaxis in human vascular smooth muscle cells. - Clunn, GF; Refson, JS; Lymn, JS; Hughes, AD
The effect of the three platelet-derived growth factor (PDGF) isoforms AA, AB, and BB on migration was investigated in cultured human saphenous vein smooth muscle cells. The modified Boyden chamber technique yielded efficacies BB > AB, AA = 0. However, the BB concentration-response relationship displayed a pronounced peak, occurring between 1 and 10 ng/mL, with no response above this range. Checkerboard analysis showed that the promotion of migration at low concentrations was chemotactic in nature but that the downturn was independent of gradient. Furthermore, at high concentrations BB was able to prevent chemotaxis induced by fetal calf serum and epidermal...
Thrombospondin-1 is a potent mitogen and chemoattractant for human vascular smooth muscle cells. - Patel, MK; Lymn, JS; Clunn, GF; Hughes, AD
Thrombospondin-1 (TSP-1) is a matricellular protein that is present in negligible amounts in normal human vasculature but occurs in significant amounts in diseased vessels. In this study, we examined the effect of TSP-1 on DNA synthesis, proliferation, and migration in human vascular smooth muscle cells grown from saphenous vein. TSP-1 (0.1 to 30 micrograms/mL) elicited a concentration-dependent increase in DNA synthesis under serum-free conditions. In combination with platelet-derived growth factor, TSP-1 induced a synergistic effect on DNA synthesis that was significantly higher than the additive effect of both agents. In proliferation assays, TSP-1 increased cell numbers by 50% relative to...
Retinal vascular network architecture in low-birth-weight men. - Chapman, N; Mohamudally, A; Cerutti, A; Stanton, A; Sayer, AA; Cooper, C; Barker, D; Rauf, A; Evans, J; Wormald, R; Sever, P; Hughes, A; Thom, S
Low birth weight is associated with hypertension and increased cardiovascular mortality, but the mechanism of this association is not known. Hypertension is accompanied by abnormalities of the microvasculature including rarefaction.
Action of losartan metabolite E-3174, tyrosine kinase inhibition and calcium channel blockade on angiotensin-II (AII) responses in human resistance arteries - Garcha, RS; Sever, PS; Hughes, AD
Losartan is an AT receptor antagonist which in humans is converted to an active metabolite, E-3174, contributing to the net AII-receptor blockade. Genistein is a tyrosine kinase inhibitor, amlodipine is a voltage-operated calcium channel antagonist, nickel inhibits voltage and receptor-operated calcium channels. The aim of this study was to examine the mechanism of action of AT receptor-induced contraction in isolated human subcutaneous resistance arteries. Human subcutaneous resistance arteries were mounted in a Mulvany myograph containing physiological saline (PSS) for the measurement of isometric tension and intracellular calcium [Ca]. For measurement of [Ca] vessels were loaded with fura-2. Data are expressed...
Effect of inhibition of tyrosine phosphatases on voltage-operated calcium channel currents in rabbit isolated ear artery cells. - Wijetunge, S; Lymn, JS; Hughes, AD
1. The effect of increasing cellular tyrosine phosphorylation by inhibiting endogenous tyrosine phosphatases was examined on voltage-operated calcium channel currents in vascular smooth muscle cells. 2. In single ear artery smooth muscle cells of the rabbit, studied by the whole cell voltage clamp technique, intracellular application of the tyrosine phosphatase inhibitors, sodium orthovanadate (100 microM) and peroxyvanadate (100 microM orthovanadate + 1 mM H2O2) increased voltage-operated calcium channel currents by 56% and 83%, respectively. 3. Bath application of two other membrane permeant tyrosine phosphatase inhibitors, phenylarsine oxide (100 microM) and dephostatin (50 microM) also increased voltage-operated calcium channel currents by...
Regulation of phospholipase C-delta by GTP-binding proteins-rhoA as an inhibitory modulator - Hodson, EAM; Ashley, CC; Hughes, AD; Lymn, JS
The regulation of Phospholipase C (PLC)δ activity remains obscure. These studies show that PLCδ activity is significantly enhanced by both guanosine thiotriphosphate (GTPγS) and Clostridium botulinum exoenzyme C3 (C3) but not by aluminium fluoride. C3 ADP ribosylated a 21-kDa protein in the PLCδ preparation and Western blotting identified rhoA in these samples. RhoA acts as an inhibitory modulator of PLCδ activity.
Vein graft stenosis and the heparin responsiveness of human vascular smooth muscle cells. - Refson, JS; Schachter, M; Patel, MK; Hughes, AD; Munro, E; Chan, P; Wolfe, JH; Sever, PS
Vascular smooth muscle cell (VMSC) proliferation is an essential component of myointimal hyperplasia, which is implicated in the failure of 30% to 50% of vascular interventions, such as coronary angioplasty and peripheral vein grafting. We have shown that cells derived from stenotic lesions in infrainguinal vein grafts were significantly more resistant than controls to growth inhibition by heparin.
Role of tyrosine phosphorylation in excitation-contraction coupling in vascular smooth muscle. - Hughes, AD; Wijetunge, S
Increasingly it is recognized that tyrosine phosphorylation plays an important part in the regulation of function in differentiated contractile vascular smooth muscle. Tyrosine kinases and phosphatases are present in large amounts in vascular smooth muscle and have been reported to influence a number of processes crucial to contraction, including ion channel gating, calcium homeostasis and sensitization of the contractile process to [Ca2+]i. This review summarizes current understanding regarding the role of tyrosine phosphorylation in excitation-contraction coupling in blood vessels.