Impaired vascular permeability regulation caused by the VEGF165b splice variant in pre-eclampsia

Show simple item record Bills, Victoria L. Salmon, Andrew H. Harper, Steven J. Overton, Tim G. Neal, Chris R. Jeffery, Bridget Soothill, Peter W. Bates, David O. 2011-10-12T07:19:24Z 2012-09-30T22:10:02Z 2011-09
dc.description.abstract OBJECTIVE: Pre-eclampsia is diagnosed by hypertension and proteinuria, probably caused by endothelial dysfunction, resulting in symptoms including oedema, inflammation and altered metabolism. Vascular endothelial growth factor A (VEGF-A) is detected at higher concentrations in plasma from patients with pre-eclampsia than in plasma from normotensive pregnant patients when determined by radioimmunoassay. This study tested the hypothesis that circulating VEGF-A in pre-eclamptic plasma is biologically active in vivo, and aimed to identify specific isoforms responsible for this activity. DESIGN: Plasma from pre-eclamptic (n = 17) and normotensive (n = 10) pregnant women was perfused into Rana mesenteric microvessels, and the subsequent change in microvascular permeability was measured using a single-vessel perfusion micro-occlusion technique. RESULTS: Pre-eclamptic but not normotensive plasma resulted in a 5.25 ± 0.8-fold acute increase in vascular permeability (P = 0.0003). This increase could be blocked by the incubation of plasma with bevacizumab, an antibody to VEGF-A (n = 7; P = 0012), and by VEGF-A receptor inhibition by SU5416 at doses specific to VEGF-A receptor-1 (VEGFR1), but not by the VEGF-A receptor-2 inhibitor, ZM323881. Although VEGF165b levels were not significantly altered in the PET samples, the increase in permeability was also inhibited by incubation of pre-eclamptic plasma with an inhibitory monoclonal antibody specific for VEGF165b (n = 6; P < 0.01), or by the addition of placental growth factor 1 (PlGF-1; n = 3; P < 0.001). PlGF-1 was detected at lower concentrations in pre-eclamptic plasma than in normotensive plasma. CONCLUSIONS: These findings suggest that circulating VEGF-A levels in pre-eclampsia are biologically active because of a loss of repression of VEGFR1 signalling by PlGF-1, and VEGF165b may be involved in the increased vascular permeability of pre-eclampsia. en_US
dc.description.sponsorship This work was supported by the British Heart Foundation (FS/05/100 to VLB and BS/06/005 to DOB), and the Medical Research Council (RD1627 to DOB/SJH, and G0802829 to AHS). en_US
dc.description.uri en_US
dc.identifier.citation Bills V, Salmon A, Harper S, Overton T, Neal C, Jeffery B, Soothill P, Bates D. Impaired vascular permeability regulation caused by the VEGF165b splice variant in pre-eclampsia. BJOG 2011;118:1253–1261. en_US
dc.identifier.issn 1470-0328 (print)
dc.identifier.issn 1471-0528 (online)
dc.identifier.other 10.1111/j.1471-0528.2011.02925.x
dc.language.iso en en_US
dc.publisher Wiley-Blackwell en_US
dc.rights © 2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2011 RCOG. The definite version is available at This article is embargoed by the publisher until September 2012. en_US
dc.subject Hydraulic conductivity en_US
dc.subject Microvascular permeability en_US
dc.subject Pre-eclampsia en_US
dc.subject Vascular endothelial growth factor en_US
dc.subject.lcsh Pregnancy -- Complications en
dc.title Impaired vascular permeability regulation caused by the VEGF165b splice variant in pre-eclampsia en_US
dc.type Preprint Article en_US

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