Abstract
Vascular endothelial growth factor receptor 2 (VEGFR-2), the primary receptor for VEGF, is crucial for normal endothelial function. sFlt-1, a truncated and soluble form of VEGFR-1 which binds and inhibits VEGF, is increased in preeclampsia and is positively regulated by low oxygen. Here, we investigated the effects of sFlt-1 and hypoxia on VEGFR-2 expression and signaling in the human placenta. VEGFR-2 transcript and protein levels were significantly decreased in preeclamptic placentae compared to controls (1.82 and 1.85 fold, respectively). An inverse correlation was observed for VEGFR-2 and sFlt-1 levels in both singleton and twin placentae from patients with preeclampsia. Immunofluorescence analyses revealed co-localization of VEGFR-2 and sFlt-1 in placental vasculature and co-immunoprecipitation analyses confirmed VEGFR-2 and sFlt-1 interaction only in preeclamptic placentae compared to age-matched controls. VEGFR-2 transcript and protein levels from explants cultured in 3% O2 were significantly decreased compared to those incubated at 20% O2 (5.9 and 12.47 fold, respectively). Also, VEGFR-2 transcript levels were significantly decreased in early first trimester placentae (low oxygen environment) compared to late first trimester placentae (2.05 fold). We next explored whether sFlt-1 directly affects VEGFR-2 expression. Treatment of first trimester placental explants with sFlt-1 resulted in significantly decreased levels of VEGFR-2 (2.03 fold) and downstream signaling proteins phospho-ERK (1.60 fold) and phospho-Akt (1.64 fold). Our findings show a novel hypoxia-induced and PE-related down-regulation of VEGFR-2 in the human placenta. sFlt-1, which is known to be increased in hypoxic conditions and PE, directly attenuates VEGFR-2 expression and signaling. A direct interaction between sFlt-1 and VEGFR-2 may represent an important mechanism in VEGFR-2 regulation, inhibition of VEGFR-2-mediated processes in placentation and a novel platform to examine the onset of preeclampsia.
Highlights
Preeclampsia is a severe complication of pregnancy characterised by increased maternal blood pressure, proteinuria, and end organ disease due to systemic vascular/endothelial dysfunction
Vascular endothelial growth factor receptor 2 (VEGFR-2) transcript levels were significantly decreased 1.82 fold in PE compared with preterm control (PTC) placentae (0.8660.12 versus 1.5760.23, P,0.05), in close approximation with the differences observed at the protein level
VEGFR-2 is a receptor tyrosine kinase that is expressed in endothelial cells and in the trophoblast layer of the human placenta; its regulation of expression in the human placenta has not yet been reported
Summary
Preeclampsia is a severe complication of pregnancy characterised by increased maternal blood pressure, proteinuria, and end organ disease due to systemic vascular/endothelial dysfunction. Soluble VEGF receptor-1 (sFlt-1) has been recognized as an important factor that is involved in the pathogenesis of preeclampsia through inducing vascular dysfunction [1]. It has been shown that placentae from patients with severe preeclampsia secrete excess sFlt-1 accompanied by markedly increased maternal sFlt-1 serums levels [1]. The primary mechanism by which sFlt-1 alters angiogenesis and induces endothelial dysfunction is thought to be by sequestering its endogenous ligands decreasing their bioavailability. SFlt-1 is a truncated splice variant of VEGF receptor-1 (VEGFR-1), a transmembrane receptor tyrosine kinase that binds both vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) with high affinity. It has been reported that in-vivo, sFlt-1 exists as several isoforms with various molecular weights between 100 and 145 kDa [3,4]
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