Inhibition of Delta-like 4 mediated signaling induces abortion in mice due to deregulation of decidual angiogenesis

Autores de IIS La Fe

• Carmen Maria Garcia Pascual

  Autor

• Hortensia Ferrero Chafer

  Autor

• Carlos Simon Valles

  Autor

• Antonio Pellicer Martínez

  Autor

Participantes ajenos a IIS La Fe

• Zimmermann RC
• Gómez R

Grupos

• Medicina Reproductiva

  

  Investigador Principal

  José Morales Roselló

Abstract

Objective: To explore whether the Dll4/Notch1 pathway plays a key role in regulating the vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) driven decidual angiogenesis and related pregnancy through induction of a tip/stalk phenotype. Methods: Progesterone-replaced ovariectomized pregnant mice received a single injection of YW152F (Dll4 blocking antibody, BAb) or placebo at embryonic day (E) 4.5. Animals were sacrificed at different time points; blood and uterus were collected for further analysis. Number of embryos and implantation site, uteri weight, and serum progesterone levels were assessed. Alterations in the tip/stalk phenotype were determined by quantitative immunofluorescent analysis of vascularization, Dll4 expression, cellular proliferation and apoptosis in uterine sections. Results: Abrogation of Dll4 signaling leads to a promiscuous expression of Dll4, increased cell proliferation, apoptosis and vascularization at E 6.5. Such an abrogation was associated with a dramatic disruption of embryo growth and development starting at E 9.5. Discussion: The observed promiscuous expression of Dll4 and the increase in cell proliferation, apoptosis and vascularization are events compatible with loss of the tip/stalk phenotype. Excessive (although very likely defective) decidual angiogenesis due to such vascular alterations is the most likely cause of subsequent interruption of embryo development and related pregnancy in Dll4 treated mice. Conclusions: Dll4 plays a key role in regulating decidual angiogenesis and related pregnancy through induction of a tip/stalk phenotype. (C) 2014 Elsevier Ltd. All rights reserved.

Keywords

• Decidua; Dll4; Notch pathway; VEGF; Angiogenesis; Pregnancy disruption