Role of the vasohibin family in the regulation of fetoplacental vascularization and syncytiotrophoblast formation

PLoS One. 2014 Sep 3;9(9):e104728. doi: 10.1371/journal.pone.0104728. eCollection 2014.


Vasohibin-1 (VASH1) and vasohibin-2 (VASH2), the 2 members of the vasohibin family, have been identified as novel regulators of angiogenesis. VASH1 ceases angiogenesis, whereas VASH2 stimulates sprouting. Here we characterized their functional role in the placenta. Immunohistochemical analysis of human placental tissue clarified their distinctive localization; VASH1 in endothelial cells and VASH2 in trophoblasts. We then used a mouse model to explore their function. Wild-type, Vash1((-/-)), and Vash2((-/-)) mice on a C57BL6 background were used in their first pregnancy. As expected, the fetal vascular area was increased in the Vash1((-/-)) mice, whereas it was decreased in the Vash2((-/-)) mice relative to wild-type. In addition, we noticed that the Vash2((-/-)) mice at 18.5dpc displayed thinner villi of the labyrinth and larger maternal lacunae. Careful observation by an electron microscopy revealed that the syncytiotrophoblast formation was defective in the Vash2((-/-)) mice. To test the possible involvement of VASH2 in the syncytiotrophoblast formation, we examined the fusion of BeWo cells, a human trophoblastoid choriocarcinoma cell line. The forskolin treatment induced the fusion of BeWo cells, and the knockdown of VASH2 expression significantly inhibited this cell fusion. Conversely, the overexpression of VASH2 by the infection with adenovirus vector encoding human VASH2 gene significantly increased the fusion of BeWo cells. Glial cell missing-1 and endogenous retrovirus envelope glycoprotein Syncytin 1 and Syncytin 2 are known to be involved in the fusion of trophoblasts. However, VASH2 did not alter their expression in BeWo cells. These results indicate that VASH1 and VASH2 showed distinctive localization and opposing function on the fetoplacental vascularization. Moreover, our study shows for the first time that VASH2 expressed in trophoblasts is involved in the regulation of cell fusion for syncytiotrophoblast formation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Adult
  • Angiogenic Proteins / genetics*
  • Angiogenic Proteins / metabolism
  • Animals
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cell Fusion
  • Cell Line, Tumor
  • Colforsin / pharmacology
  • DNA-Binding Proteins
  • Female
  • Gene Expression Regulation
  • Gene Products, env / genetics
  • Gene Products, env / metabolism
  • Genetic Vectors
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neovascularization, Physiologic*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Pregnancy
  • Pregnancy Proteins / genetics
  • Pregnancy Proteins / metabolism
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Trophoblasts / cytology
  • Trophoblasts / drug effects
  • Trophoblasts / metabolism*


  • Angiogenic Proteins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • ERVFRD-1 protein, human
  • GCM1 protein, human
  • Gene Products, env
  • Nuclear Proteins
  • Pregnancy Proteins
  • Transcription Factors
  • VASH1 protein, human
  • VASH2 protein, human
  • syncytin
  • Colforsin

Grants and funding

This work was supported by a grant from the Global COE for Conquest of Signal Transduction Diseases with Network Medicine, Tohoku University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.