Our data suggest that VEGF A

Our data suggest that VEGF-A inhibits venous identity in adult EC, recapitulating the change seen during vein graft AdipoRon in vivo. Vein graft adaptation to the arterial environment may depend on the plasticity of adult EC, and their ability to integrate VEGF signaling pathways, to properly modify the vessel phenotype. In addition, we show that EphB4 is a negative repressor of VEGF-induced reduced EphB4 expression and increased dll4 expression. This finding may provide a basis for EphB4 retention of venous identity in adult EC.
Acknowledgment This work was supported by the National Institute of Health (R01-HL095498 to A.D.), the American Vascular Association William J. von Liebig Award, and with the resources and the use of facilities at the VA Connecticut Healthcare System, West Haven, CT. The authors have no conflicts of interest to declare.
Introduction Maintaining the normal function of fetal trophoblasts is essential for a successful pregnancy. Preeclampsia (PE), a pregnancy-specific disorder, is often associated with excessive trophoblast cell apoptosis and superficial trophoblast invasion leading to insufficient spiral artery remodeling and placental hypoxia [[1], [2], [3]]. PE is characterized by new onset hypertension and proteinuria affecting 5–8% of all pregnancies worldwide and representing a leading cause of maternal and perinatal morbidity and mortality [4,5]. Multiple factors have been suggested for the development and progression of PE, however, the precise molecular pathogenesis of PE remains largely unknown [6]. Understanding the genetic and epigenetic alterations involved in trophoblast cell behaviors would help in the development of novel therapeutic targets for the treatment of PE. MicroRNAs (miRNAs) are a class of conserved and non-coding RNAs that regulate gene expression by post-transcriptional repression [7]. The mature miRNAs consisting of 21–25 nucleotides can bind to the 3’-untranslated region (3’-UTR) of target mRNAs in a base-pairing manner, leading to mRNA instability, degradation, and translational repression [8]. Through targeting and regulating target genes, miRNAs can regulate various cellular processes involved in the normal development and onset of diseases [9]. Accumulating evidence has suggested that numerous miRNAs are differentially expressed in human placentas from PE patients [10,11], indicating their potential role in the pathogenesis of PE. Recent studies have reported that miRNAs are involved in regulation of the proliferation, apoptosis, migration, and invasion of trophoblast cells [[12], [13], [14], [15]]. Therefore, a better understanding the role of miRNA in regulating trophoblast cell behaviors may shed light on development of novel biomarkers for PE diagnosis as well as targets for treatment. Ephrin receptor B4 (EPHB4) is a member of the receptor tyrosine kinase superfamily [16] and is expressed in endothelial cells of the venous lineage and plays an important role in various diseases [[17], [18], [19]]. Increasing studies have reported that EPHB4 plays a critical role during placentation [[20], [21], [22]]. EPHB4 has been found to regulate the proliferation, apoptosis, migration, and invasion of trophoblast cells involved in the pathogenesis of PE [23,24]. Therefore, EPHB4 may have the potential to be used as a therapeutic target for PE.