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Impaired vascular permeability regulation caused by the VEGF 165 b splice variant in pre‐eclampsia
Author(s) -
Bills VL,
Salmon AH,
Harper SJ,
Overton TG,
Neal CR,
Jeffery B,
Soothill PW,
Bates DO
Publication year - 2011
Publication title -
bjog: an international journal of obstetrics and gynaecology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.157
H-Index - 164
eISSN - 1471-0528
pISSN - 1470-0328
DOI - 10.1111/j.1471-0528.2011.02925.x
Subject(s) - medicine , endocrinology , vascular permeability , vascular endothelial growth factor , receptor , preeclampsia , incubation , eclampsia , chemistry , biology , vegf receptors , pregnancy , biochemistry , genetics
Please cite this paper as: Bills V, Salmon A, Harper S, Overton T, Neal C, Jeffery B, Soothill P, Bates D. Impaired vascular permeability regulation caused by the VEGF 165 b splice variant in pre‐eclampsia. BJOG 2011; DOI: 10.1111/j.1471‐0528.2011.02925.x. 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 VEGF 165 b 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 VEGF 165 b ( 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 VEGF 165 b may be involved in the increased vascular permeability of pre‐eclampsia.