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


CONCLUSIONS
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.
Fundación IVI, Instituto Universitario IVI/INCLIVA, 46015, C/Catedrático Agustín Escardino n° 9, PARC CIENTIFIC UNIVERSITAT DE VALENCIA Edificio 3, CUE. 2ª Planta. Despacho 2.02, 46980 Paterna (Valencia), Spain.
C M
CM
García-Pascual
Fundación IVI, Instituto Universitario IVI/INCLIVA, 46015, C/Catedrático Agustín Escardino n° 9, PARC CIENTIFIC UNIVERSITAT DE VALENCIA Edificio 3, CUE. 2ª Planta. Despacho 2.02, 46980 Paterna (Valencia), Spain.
H
H
Ferrero
Department of Obstetrics and Gynecology, Columbia University, 630 West 168th Street, New York 10032, United States. Electronic address: rcz3@columbia.edu.
R C
RC
Zimmermann
Fundación IVI, Instituto Universitario IVI/INCLIVA, 46015, C/Catedrático Agustín Escardino n° 9, PARC CIENTIFIC UNIVERSITAT DE VALENCIA Edificio 3, CUE. 2ª Planta. Despacho 2.02, 46980 Paterna (Valencia), Spain.
C
C
Simón
Fundación IVI, Instituto Universitario IVI/INCLIVA, 46015, C/Catedrático Agustín Escardino n° 9, PARC CIENTIFIC UNIVERSITAT DE VALENCIA Edificio 3, CUE. 2ª Planta. Despacho 2.02, 46980 Paterna (Valencia), Spain.
A
A
Pellicer
Fundación IVI, Instituto Universitario IVI/INCLIVA, 46015, C/Catedrático Agustín Escardino n° 9, PARC CIENTIFIC UNIVERSITAT DE VALENCIA Edificio 3, CUE. 2ª Planta. Despacho 2.02, 46980 Paterna (Valencia), Spain.
R
R
Gómez
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D017209:Apoptosis; D002135:Calcium-Binding Proteins; D049109:Cell Proliferation; D003656:Decidua / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D020964:Embryo Loss / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D047108:Embryonic Development; D005260:Female; D005865:Gestational Age; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D051379:Mice; D018919:Neovascularization, Physiologic; D011247:Pregnancy; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D019138:Antibodies, Blocking; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2
Angiogenesis; Decidua; Dll4; Notch pathway; Pregnancy disruption; VEGF