title: Impaired vascular permeability regulation caused by the VEGF₁₆₅b splice variant in pre-eclampsia.
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.
  
  
  METHODS
  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 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.
authors.affiliation: Microvascular Research Laboratories, Bristol Heart Institute, Department of Physiology and Pharmacology, University of Bristol, School of Veterinary Sciences, Bristol, UK. Victoria.bills@nhs.net
authors.forename: V L
authors.initials: VL
authors.lastname: Bills
authors.forename: A H
authors.initials: AH
authors.lastname: Salmon
authors.forename: S J
authors.initials: SJ
authors.lastname: Harper
authors.forename: T G
authors.initials: TG
authors.lastname: Overton
authors.forename: C R
authors.initials: CR
authors.lastname: Neal
authors.forename: B
authors.initials: B
authors.lastname: Jeffery
authors.forename: P W
authors.initials: PW
authors.lastname: Soothill
authors.forename: D O
authors.initials: DO
authors.lastname: Bates
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D001681:Biological Assay; D002199:Capillary Permeability / Q000502:physiology*; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000097:blood; D011225:Pre-Eclampsia / Q000097:blood*; D011247:Pregnancy; D011799:Quinazolines / Q000494:pharmacology; D011898:Ranidae; D042461:Vascular Endothelial Growth Factor A / Q000097:blood* / Q000276:immunology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D008565:Membrane Proteins; C098069:PIGF protein, human; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; C478783:ZM323881; D000068258:Bevacizumab; D040281:Vascular Endothelial Growth Factor Receptor-1