The endogenous anti-angiogenic family of splice variants of VEGF, VEGFxxxb, are down-regulated in pre-eclamptic placentae at term.
PET (pre-eclamptic toxaemia) has recently been linked with alterations in production of a VEGFR1 [VEGF (vascular endothelial growth factor) receptor 1] splice variant that acts as a circulating inhibitor. We have recently described a family of naturally occurring splice variants of VEGF, termed VEGFxxxb, that also appear to act as inhibitors of conventional VEGFxxx-mediated angiogenesis. To determine whether alteration in splicing of VEGF-VEGFR family members extended beyond VEGFR1, we investigated the effect of pre-eclampsia on placental VEGFxxxb mRNA and protein expression. VEGFxxx and VEGFxxxb mRNA and protein were both found in normal human term placentae. VEGFxxx protein formed the majority of the total VEGF protein (980+/-195 pg/mg), whereas VEGFxxxb (11.5 pg/mg) was found to form a small part of the total VEGF protein expression (1.5+/-0.24%). Evidence for VEGF165b, VEGF121b and VEGF145b expression was found. In pre-eclamptic placentae, there was a significant down-regulation of VEGFxxxb isoforms, but a small up-regulation of VEGFxxx isoforms. In normal placenta VEGFxxxb and VEGFxxx concentrations were positively correlated (r=0.69, P<0.02), whereas in pre-eclamptic placentae, there was a significant negative correlation between VEGFxxxb and VEGFxxx protein expression (r=-0.8, P<0.02), indicating that there was a significant uncoupling of the splicing regulation of the VEGF isoforms. Combined with previous studies showing increased soluble VEGFR1 isoforms in human pre-eclampsia, these data suggest that there may be a common mechanism in pre-eclampsia that involves dysregulation of mRNA splicing of members of the VEGF-VEGFR axis.
Bates
David O
DO
Microvascular Research Laboratories, Department of Physiology, Preclinical Veterinary School, University of Bristol, Bristol BS2 8EJ, UK. Dave.Bates@bristol.ac.uk
MacMillan
Philip P
PP
Manjaly
Joseph G
JG
Qiu
Yan
Y
Hudson
Sarah J
SJ
Bevan
Heather S
HS
Hunter
Alyson J
AJ
Soothill
Peter W
PW
Read
Michael
M
Donaldson
Lucy F
LF
Harper
Steven J
SJ
D000293:Adolescent; D000328:Adult; D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D010920:Placenta / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015854:Up-Regulation; D042442:Vascular Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism*
D020533:Angiogenesis Inhibitors; D020033:Protein Isoforms; D012333:RNA, Messenger; D042442:Vascular Endothelial Growth Factors