J Brockelsby

University of Nottingham, Nottigham, England, United Kingdom

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Publications (7)17.05 Total impact

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    ABSTRACT: A leading theory of the pathophysiology of preeclampsia is that oxidative stress induces vascular endothelial cell dysfunction. Advanced glycation end products (AGEs) form when aldose sugars react nonenzymatically with proteins under conditions of oxidative stress. AGEs are circulating molecules and can generate reactive oxygen species and vascular dysfunction (in diabetes and atherosclerosis) through an association with cell surface receptors (RAGE). RAGE is a multiligand receptor, expressed in vascular tissue, which is upregulated by its own ligands. Insulin resistance and obesity are risk factors for developing preeclampsia, as well as being conditions that would increase RAGE levels. Thus, we hypothesized that women with preeclampsia will have elevated levels of RAGE protein compared with normal pregnant women. Biopsies of nonlaboring myometrium as well as omentum were taken from normal pregnant and preeclamptic women. Nonpregnant samples were obtained at the time of hysterectomy. Tissue sections were immunostained with anti-RAGE as well as anti-alpha-actin and anti-von Willebrand factor (to identify blood vessels and intact endothelial cells). Staining intensity was qualitatively described as well as given an intensity score, with the identity of the section concealed. Nonpregnant myometrial and omental vessels showed very low to undetectable levels of RAGE staining. Pregnancy induced a significant increase in RAGE protein levels in both myometrium and omental vasculature. Blood vessels from women with preeclampsia consistently had intense staining for RAGE in both vessel beds. Thus, our data suggest that since RAGE activation can induce similar pathophysiologic changes to those observed in women with preeclampsia (including NFkappaB activation, increased TNFalpha and endothelin), elevated RAGE protein may be contributing to the vascular dysfunction in preeclampsia.
    Hypertension in Pregnancy 02/2003; 22(2):173-84. · 0.93 Impact Factor
  • J C Brockelsby, F W Anthony, I R Johnson, P N Baker
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    ABSTRACT: Preeclampsia is primarily a disorder of the maternal endothelium. An as yet unidentified circulating factor causes widespread alteration in endothelial function, and levels of vascular endothelial growth factor are elevated in preeclampsia. We hypothesized that vascular endothelial growth factor is involved in the alteration of endothelial function and set out to find further evidence for this contention. Bovine microvascular endothelial cells (B-88) were cultured in vitro. These cultured cells were then stimulated with vascular endothelial growth factor and with plasma from women with preeclampsia in the presence and absence of anti-vascular endothelial growth factor antibody. Prostacyclin, nitric oxide, and lactate dehydrogenase levels were measured. Vascular endothelial growth factor induced a significant concentration-dependent increase in prostacyclin production but not nitric oxide production. Cells stimulated with plasma from women with preeclampsia showed increases in production of both prostacyclin and nitric oxide. Vascular endothelial growth factor concentration in plasma was correlated with prostacyclin production by stimulated cells. The increase in prostacyclin production that usually followed the addition of plasma did not occur when anti-vascular endothelial growth factor antibody was present. Vascular endothelial growth factor has the ability to alter endothelial cell function in a manner analogous to that of plasma from women with preeclampsia.
    American Journal of Obstetrics and Gynecology 02/2000; 182(1 Pt 1):176-83. · 3.88 Impact Factor
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    R Hayman, A Warren, J Brockelsby, I Johnson, P Baker
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    ABSTRACT: To compare the in vitro effect of plasma from normal pregnant women and women with pre-eclampsia on the endothelium-dependent behaviour of myometrial resistance arteries from normal pregnant women. An in vitro comparative study. Nottingham City Hospital. Uterine biopsy specimens were obtained from normal pregnant women delivered by elective caesarean section at term. Plasma was collected from nulliparous women with pre-eclampsia (n = 18), and from multiparous normal pregnant women (n = 18), all samples being matched for maternal age and gestation at venepuncture. Pools of plasma from women with pre-eclampsia and normal pregnant women were formed from these samples and were used in all the experiments. Myometrial resistance vessels obtained from the uterine biopsies were incubated with normal pregnant plasma, plasma from women with pre-eclampsia, or without plasma. Wire myography was employed to study the effect of plasma on the endothelium-dependent behaviour of these vessels. Incubation of vessels from normal pregnant women with plasma from women with pre-eclampsia resulted in a significant reduction in endothelium-dependent relaxation, compared with vessels incubated either with plasma from normal pregnant women or without plasma. This alteration in endothelial function occurred after an incubation period of one hour and required a threshold concentration for its effect to become established. Removal of the vascular endothelium abolished these changes in vessel behaviour. There were no plasma-induced alterations in the endothelium-independent behaviour of the vascular smooth muscle. This study supports the hypothesis that plasma from women with pre-eclampsia is capable of altering endothelium-dependent myometrial relaxation in vessels from pregnant women.
    BJOG An International Journal of Obstetrics & Gynaecology 02/2000; 107(1):108-15. · 3.76 Impact Factor
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    ABSTRACT: Preeclampsia is a multisystem disorder characterized by hypertension and proteinuria. There is accumulating evidence that this is a disease of the endothelium, with an as-yet unidentified circulating factor, or factors, causing the observed alteration in vascular function. We previously reported that the function of myometrial vessels is altered on exposure to plasma from women with preeclampsia. Vascular endothelial growth factor (VEGF) is an angiogenic growth factor that acts via two high-affinity receptors (KDR and Flt-1), and its production is increased in preeclampsia. Here we report that VEGF and its Flt-1 receptor may play a pivotal role in the altered vascular function of preeclampsia. Myometrial resistance vessels were obtained at the time of cesarean section. Using the Mulvany wire myograph, the endothelium-dependent behavior of these vessels was studied. Incubation of vessels from pregnant women with VEGF resulted in a reduction of endothelium-dependent relaxation that mimicked the reduction induced by plasma from women with preeclampsia. The altered function that occurred upon exposure of vessels to VEGF or plasma from women with preeclampsia did not occur when plasma was incubated with antibodies to VEGF before vessel incubation. The presence of an anti-KDR receptor antibody had no effect on VEGF response. However, in the presence of an anti-Flt-1 receptor antibody, VEGF or plasma from women with preeclampsia no longer attenuated the endothelium-dependent relaxation (p < 0.05). The changes observed with VEGF and plasma from women with preeclampsia and their subsequent blockade with anti-VEGF antibody and anti-Flt-1 receptor antibody strongly suggest that VEGF acting through the Flt-1 receptor is pivotal in the pathogenesis of this disease.
    Laboratory Investigation 10/1999; 79(9):1101-11. · 3.96 Impact Factor
  • R Hayman, J Brockelsby, L Kenny, P Baker
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    ABSTRACT: It has been proposed that endothelial cell activation is the primary event in the multisystem disorder of preeclampsia. Evidence for endothelial involvement in this condition abounds. The best-characterized morphologic abnormality of this syndrome, glomerular endotheliosis, involves endothelial cells. Also associated with preeclampsia is a loss of endothelial cell integrity, with the consequent increase in vascular permeability, and an increase in the circulating levels of the endothelial cell markers, fibronectin, von Willebrand factor, tissue plasminogen activator, and plasminogen activator inhibitor-1. It is now well documented that endothelial activation contributes to the coagulation abnormalities observed in this disease. There is much evidence that the endothelial alterations in preeclampsia result from one or more circulating factors. The incubation of cultured endothelial cells with serum or plasma samples, taken from normal pregnant women and women with preeclampsia, results in marked alterations in cell behavior and metabolic processes. More recently, experiments employing myographic techniques have demonstrated convincingly the effects of a circulating factor(s) on the function of endothelial cells of resistance arteries. Vascular endothelial growth factor (VEGF) possesses many of the characteristics required of a candidate circulating factor. It contains a hydrophobic secretory signal sequence, exerts in vitro effects specific to vascular endothelial cell, and promotes endothelial expression of procoagulant activity. Circulating VEGF concentrations are elevated in women with preeclampsia, and VEGF increases microvascular endothelial cell prostacyclin production in a dose-dependent manner, analogous to the acute effects of plasma from patients with preeclampsia. Similarly, in myographic studies, when myometrial resistance arteries are incubated with VEGF, there are dose-dependent alterations in endothelium-dependent behavior, mirroring those found after incubation with plasma from patients with preeclampsia.
    Journal of the Society for Gynecologic Investigation 01/1999; 6(1):3-10. · 2.26 Impact Factor
  • R P Wellings, J C Brockelsby, P N Baker
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    ABSTRACT: To compare the ability of plasma from a population of women with preeclampsia and a population of plasma from women with normal pregnancies to activate four different endothelial cell types. The secretion of nitrite and 6-keto prostaglandin F1 alpha by four endothelial cell types (isolated from the microvasculature of human decidua and skin, as well as a human umbilical vein endothelial cell line and a bovine coronary microvascular cell line) was assessed following a 24-hour incubation with plasma samples from the two groups. Nitrite production (an indicator of nitric oxide release) was detectable in only the decidual endothelial cells and the bovine microvascular endothelial cells (B-88), whereas 6-keto prostaglandin F1 alpha (stable metabolite of prostacyclin) was detectable in all cells. Only in the B-88 cells was there a greater production of nitrite or 6-keto prostaglandin F1 alpha in response to incubation with plasma from the preeclamptic patients when compared to plasma from the normotensive controls. The different responses of various endothelial cell types to the activating effects of plasma from preeclamptic women indicate that another important caveat to be considered when bioassaying for the circulating factor(s) of preeclampsia is the choice of endothelial cell to be studied.
    Journal of the Society for Gynecologic Investigation 01/1998; 5(1):31-7. · 2.26 Impact Factor
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    ABSTRACT: Objective: To determine whether levels of vascular endothelial growth factor (VEGF) are raised in pregnancies complicated by preeclampsia. Methods: Samples of serum were collected from 10 patients with preeclampsia and 10 gestation-matched normotensive controls. Levels of VEGF were measured in samples using a radioimmunoassay with a polyclonal antibody capable of recognizing all VEGF isoforms. Results: Vascular endothelial growth factor was detectable in all samples assayed. The median serum concentration of VEGF in the preeclamptic subjects was 5.1 μg/L (interquartile range: 4.7-5.5 μg/L) and for the control group 3.9 μg/L (interquartile range: 3.4-4.1 μg/L). Serum VEGF levels were significantly higher (p < 0.001, Mann-Whitney U-test) in the preeclamptic subjects. Conclusion: The raised circulating levels of VEGF in preeclampsia and the known effects of this growth factor on endothelial cell function suggest that VEGF may be involved in the pathophysiology of this disease.
    Hypertension in Pregnancy - HYPERTENS PREGNANCY. 01/1998; 17(3):283-290.